Cycloalkano-indole and -azaindole derivatives

ABSTRACT

Cycloalkano-indole and -azaindole derivatives are prepared by reaction of appropriately substituted carboxylic acids with amines. The cycloalkano-indole and -azaindole derivatives are suitable as active compounds for medicaments, preferably antiatherosclerotic medicaments.

The present invention relates to cycloalkano-indole and -azaindolederivatives, processes for their preparation and their use asmedicaments, in particular as antiatherosclerotic medicaments.

It is known that increased blood levels of triglycerides(hypertriglyceridaemia) and cholesterol (hypercholesterolaemia) areassociated with the genesis of atherosclerotic vessel wall changes andcoronary heart diseases.

A distinctly increased risk of the development of coronary heart diseaseis moreover present if these two risk factors occur in combination,which is accompanied, in turn, with an overproduction of apolipoproteinB-100. There is therefore, as before, a great need to make availableeffective medicaments for the control of atherosclerosis and coronaryheart diseases.

The present invention relates to cycloalkano-indole and -azaindolederivatives of the general formula (I) ##STR1## in which R¹ and R²,including the double bond connecting them, together form a phenyl orpyridyl ring or a ring of the formula ##STR2## wherein R⁸ denoteshydrogen or straight-chain or branched alkyl having up to 4 carbonatoms,

R³ and R⁴, including the double bond connecting them, together form aphenyl ring or a 4- to 8-membered cycloalkene or oxocycloalkene radical,

all ring systems mentioned under R¹ /R² and R³ /R⁴ optionally beingsubstituted up to 3 times by identical or different halogen,trifluoromethyl, carboxyl or hydroxyl substituents, by straight-chain orbranched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms or bystraight-chain or branched alkyl having up to 6 carbon atoms, which, forits part, can be substituted by hydroxyl or by straight-chain orbranched alkoxy having up to 4 carbon atoms,

D represents hydrogen, cycloalkyl having 4 to 12 carbon atoms orstraight-chain or branched alkyl having up to 12 carbon atoms,

E represents the --CO-- or --CS-- group,

L represents an oxygen or sulphur atom or a group of the formula --NR⁹,

wherein

R⁹ denotes hydrogen or straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by hydroxyl or phenyl,

R⁵ represents phenyl or a 5- to 7-membered saturated or unsaturatedheterocycle having up to 3 heteroatoms from the series consisting of S,N and/or O, the cycles optionally being substituted up to 3 times byidentical or different nitro, carboxyl, halogen or cyano substituents orby straight-chain or branched alkenyl or alkoxycarbonyl each having upto 6 carbon atoms or by straight-chain or branched alkyl having up to 6carbon atoms, which is optionally substituted by hydroxyl, carboxyl orby straight-chain or branched alkoxy or alkoxycarbonyl each having up to6 carbon atoms,

and/or the cycles optionally being substituted by a group of the formula--OR¹⁰ or --NR¹¹ R¹²,

wherein

R¹⁰ denotes hydrogen or straight-chain or branched alkyl or alkenyl eachhaving up to 6 carbon atoms,

R¹¹ and R¹² are identical or different and denote phenyl, hydrogen orstraight-chain or branched alkyl having up to 6 carbon atoms orstraight-chain or branched acyl having up to 8 carbon atoms, which isoptionally substituted by a group of the formula --NR¹³ R¹⁴,

wherein

R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 8 carbon atoms,

R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 5 carbon atoms,

or represents straight-chain or branched alkyl having up to 6 carbonatoms, which is optionally substituted by hydroxyl or by a group of theformula --O--CO--R¹⁵,

wherein

R¹⁵ denotes phenyl which is optionally substituted up to 3 times byidentical or different halogen or hydroxyl substituents or bystraight-chain or branched alkyl having up to 5 carbon atoms,

or straight-chain or branched alkyl or alkenyl each having up to 22carbon atoms, each of which is optionally substituted by a group of theformula --OR¹⁶,

wherein

R¹⁶ is hydrogen, benzyl, triphenylmethyl or straight-chain or branchedacyl having up to 6 carbon atoms,

R⁷ represents hydrogen or

R⁶ and R⁷ together represent the group of the formula ═O,

if appropriate in an isomeric form, and their salts.

The cycloalkano-indole and -azaindole derivatives according to theinvention can also be present in the form of their salts. In general,salts with organic or inorganic bases or acids may be mentioned here.

In the context of the present invemion, physiologically acceptable saltsare preferred. Physiologically acceptable salts of the compoundsaccording to the invention can be salts of the substances according tothe invention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts are, for example, those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention which have a flee carboxylgroup. Particularly preferred salts are, for example, sodium, potassium,magnesium or calcium salts, and also ammonium salts which are derivedfrom ammonia, or organic amines, such as, for example ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine, ethylenediamine or2-phenylethylamine.

Including the double bond of parent structure, the cycloalkene radical(R³ /R⁴) in the context of the invention in general represents a 4- to8-membered hydrocarbon radical, preferably a 5- to 8-memberedhydrocarbon radical, for example a cyclobutene, cyclopentene,cyclohexene, cycloheptene or cyclooctene radical. The cyclopentene,cyclohexene, cyclooctene or cycloheptene radicals are preferred

Heterocycle (R⁵) in the context of the invention in general represents asaturated or unsaturated 5- to 7-membered heterocycle, preferably a 5-to 6-membered heterocycle, which can contain up to 3 heteroatoms fromthe series consisting of S, N and/or O. Examples which may be mentionedare: pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidamlyl,morpholinyl or piperidyl. Pyridyl and thienyl are preferred.

The compounds according to the invention can exist in stereoisomericforms which either behave as image and mirror image (enantiomers), or dowhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers and diastereomers and theirrespective mixtures. These mixtures of the enantiomers and diastereomerscan be separated in a known manner into the stereoisomerically uniformconstituents.

Preferred compounds of the general formula (I) are those in which

R¹ and R², including the double bond connecting them, together form aphenyl or pyridyl ring or a ring of the formula ##STR3## wherein R⁸denotes hydrogen or straight-chain or branched alkyl having up to 3carbon atoms,

R³ and R⁴, including the double bond connecting them, together form aphenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene,oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocycloocteneradical,

all ring systems mentioned under R¹ /R² and R³ /R⁴ optionally beingsubstituted up to 2 times by identical or different fluorine, chlorine,bromine, trifluoromethyl, carboxyl or hydroxyl substituents, bystraight-chain or branched alkoxy or alkoxycarbonyl each having up to 4carbon atoms or by straight-chain or branched alkyl having up to 4carbon atoms, which, in turn, can be substituted by hydroxyl or bystraight-chain or branched alkoxy having up to 3 carbon atoms,

D represents hydrogen, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl or straight-chain or branched alkyl having up to 10 carbonatoms,

E represents the --CO-- or --CS-- group,

L represents an oxygen or sulphur atom or represents a group of theformula --NR⁹,

wherein

R⁹ denotes hydrogen or straight-chain or branched alkyl having up to 5carbon atoms, which is optionally substituted by hydroxyl or phenyl,

R⁵ represents phenyl, pyridyl, furyl, thienyl or imidazolyl, each ofwhich is optionally substituted up to 2 times by identical or differentnitro, carboxyl, fluorine, chlorine, bromine or cyano substituents, bystraight-chain or branched alkenyl or alkoxy carbonyl each having up to4 carbon atoms or by straight-chain or branched alkyl having up to 5carbon atoms, which is optionally substituted by hydroxyl, carboxyl orby straight-chain or branched alkoxy or alkoxycarbonyl each having up to5 carbon atoms,

and/or the cycles are optionally substituted by a group of the formula--OR¹⁰ or --NR¹¹ R¹²,

wherein

R¹⁰ denotes hydrogen or straight-chain or branched alkyl or alkenyl eachhaving up to 4 carbon atoms,

R¹¹ and R² are identical or different and denote phenyl, hydrogen orstraight-chain or branched alkyl having up to 5 carbon atoms

or denote straight-chain or branched acyl having up to 6 carbon atoms,which is optionally substituted by a group of the formula --NR¹³ R¹⁴,

wherein

R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 6 carbon atoms,

R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 4 carbon atoms,

or represents straight-chain or branched alkyl having up to 5 carbonatoms, which is optionally substituted by hydroxyl or by a group of theformula --O--CO--R¹⁵,

wherein

R¹⁵ denotes phenyl which is optionally substituted up to 3 times byidentical or different fluorine, chlorine, bromine or hydroxylsubstituents or by straight-chain or branched alkyl having up to 4carbon atoms,

or straight-chain or branched alkyl or alkenyl each having up to 20carbon atoms, each of which is optionally substituted by a group of theformula --OR¹⁶,

wherein

R¹⁶ is hydrogen, benzyl, triphenylmethyl or straight-chain or branchedacyl having up to 5 carbon atoms,

R⁷ represents hydrogen or

R⁶ and R⁷ together represent the group of the formula ═O,

if appropriate in an isomeric form, and their salts.

Particularly preferred compounds of the general formula (I) are those inwhich

R¹ and R², including the double bond connecting them, together form aphenyl or pyridyl ring or a ring of the formula ##STR4## wherein R⁸denotes hydrogen or methyl,

R³ and R⁴, including the double bond connecting them, together form aphenyl ring or a cyclopentene, cyclohexene, cycloheptene, cyclooctene,oxocyclopentene, oxocyclohexene, oxocycloheptene or oxocycloocteneradical,

all ring systems mentioned under R¹ /R² and R³ /R⁴ optionally beingsubstituted up to 2 times by identical or different fluorine, chlorine,bromine, trifluoromethyl, carboxyl or hydroxyl substituents, bystraight-chain or branched alkoxy or alkoxycarbonyl each having up to 3carbon atoms or by straight-chain or branched alkyl having up to 3carbon atoms, which, for its part, can be substituted by hydroxyl,methoxy or ethoxy,

D represents hydrogen, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctylor straight-chain or branched alkyl having up to 6 carbon atoms,

E represents the --CO-- or --CS-- group,

L represents an oxygen or sulphur atom or represents a group of theformula --NR⁹,

wherein

R⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4carbon atoms, which is optionally substituted by hydroxyl or phenyl,

R⁵ represents phenyl, pyridyl or thienyl, each of which is optionallysubstituted up to 2 times by identical or different nitro, carboxyl,fluorine, chlorine, bromine or cyano substituents, by straight-chain orbranched alkenyl or aikoxycarbonyl each having up to 3 carbon atoms orby straight-chain or branched alkyl having, up to 4 carbon atoms, whichis optionally substituted by hydroxyl, carboxyl or by straight-chain orbranched alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,and/or the cycles are optionally substituted by a group of the formula--OR¹⁰ or --NR¹¹ R¹²,

wherein

R¹⁰ denotes hydrogen or straight-chain or branched alkyl or alkenyl eachhaving up to 3 carbon atoms,

R¹¹ and R¹² are identical or different and denote phenyl, hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms

or denote straight-chain or branched acyl having up to 5 carbon atoms,which is optionally substituted by a group of the formula --NR¹³ R¹⁴,

wherein

R¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 5 carbon atoms,

R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 3 carbon atoms,

or represents straight-chain or branched alkyl having up to 4 carbonatoms, which is optionally substituted by hydroxyl or by a group of theformula --CO--R¹⁵,

wherein

R¹⁵ denotes phenyl which is optionally substituted up to 3 times byidentical or different straight-chain or branched alkyl having up to 3carbon atoms,

or denotes straight-chain or branched alkyl or alkegyl each having up to19 carbon atoms, each of which is optionally substituted by a group ofthe formula --OR¹⁶,

wherein

R¹⁶ denotes hydrogen, benzyl, triphenylmethyl or straight-chain orbranched acyl having up to 4 carbon atoms,

R⁷ represents hydrogen or

R⁶ and R⁷ together represent the group of the formula ═O,

if appropriate in an isomeric form, and their salts.

A process for the preparation of the compounds of the general formula(I) according to the invention has additionally been found,characterized in that

carboxylic acids of the general formula (II) ##STR5## in which R¹, R²,R³, R⁴ and D have the meaning indicated,

are amidated using compounds of the general formula (III) ##STR6## inwhich R⁵ has the meaning indicated and

R¹⁷ has the indicated meaning of R⁶, but does not represent carboxyl,

in an inert solvent and in the presence of bases and/or auxiliaries,

and, if appropriate, functional groups are varied by hydrolysis,esterification or reduction.

The process according to the invention can be illustrated by thefollowing reaction scheme: ##STR7##

Suitable solvents for the amidation are in this case inert organicsolvents which do not change under the reaction conditions. Theseinclude ethers, such as diethyl ether or tetrahydrofuran,halogenohydrocarbons such as dichloromethane, trichloromethane,tetrachloromethane, trichloroethane, tetrachloroethane,1,2-dichloroethane or trichloroethylene, hydrocarbons such as benzene,xylene, toluene, hexane, cyclohexane or petroleum fractions,nilromethane, dimethylformamide, acetone, acetonilrile orhexamethylphosphoramide. It is also possible to employ mixtures of thesolvents. Dichloromethane, tetrahydrofuran, acetone anddimethylformamide are particularly preferred.

Bases which can, be employed for the process according to the inventionare in general inorganic or organic bases. These preferably includealkali metal hydroxides such as, for example, sodium hydroxide orpotassium hydroxide, alkaline earth metal hydroxides, such as, forexample, barium hydroxide, alkali metal carbonates such as sodiumcarbonate or potassium carbonate, alkaline earth metal carbonates suchas calcium carbonate, or alkali metal alkoxides such as sodium orpotassium methoxide, sodium or potassium ethoxide or potassiumtert-butoxide, or organic amines (trialkyl(C₁ -C₆)amines) such astriethylamine, or heterocycles such as 1,4-diazabicyclo 2.2.2!octane(DABCO), 1,8-diazabicyclo 5.4.0!undec-7-ene (DBU), pyridine,diaminopyridine, methylpiperidine or morpholine. It is also possible toemploy alkali metals such as sodium and their hydrides such as sodiumhydride as bases. Sodium and potassium carbonate and triethylamine arepreferred.

The base is employed in an amount from 1 mol to 5 mol, preferably from 1mol to 3 mol, relative to 1 mol of the compound of the general formula(II).

The reaction is in general carried out in a temperature range from 0° C.to 150° C., preferably from +20° C. to +110° C.

The reaction can be carried out at normal, increased or reduced pressure(e.g. 0.5 to 5 bar). In general, the reaction is carried out at normalpressure.

The amidation can optionally proceed via the activated stage of the acidhalides, which can be prepared from the corresponding acids by reactionwith thionyl chloride, phosphorus trichloride, phosphorus pentachloride,phosphorus tribromide or oxalyl chloride.

The abovementioned bases can optionally also be employed for theamidation as acid-binding auxiliaries.

Suitable auxiliaries are also dehydrating reagents. These include, forexample, carbodiimides such as diisopropylcarbodiimide,dicyclohexylcarbodiimide andN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride or carbonylcompounds such as carbonyldiimidazole or 1,2-oxazolium compounds such as2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or propanephosphonicanhydride or iso-butyl chloroformate orbenzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate ordiphenyl phosphoramidate or methanesulphonyl chloride, if appropriate inthe presence of bases such as triethylamine or N-ethylmorpholine orN-methylpiperidine or dicyclohexylcarbodiimide and N-hydroxysuccinimide.

The acid-binding agents and dehydrating reagents are in general employedin an mount from 0.5 to 3 mol, preferably from 1 to 1.5 mol, relative to1 mol of the corresponding carboxylic acids.

The variation of functional groups, for example hydrolysis,esterification and reduction, and also separation of isomers and saltformation is carried out by customary methods.

The carboxylic acids of the general formula (II) are new and can beprepared by reacting

compounds of the general formula (IV) ##STR8## in which D has themeaning indicated,

T represents a typical leaving group, for example chlorine, bromine,iodine, tosylate or mesylate, preferably bromine, and

R¹⁸ represents (C₁ -C₄)-alkyl

with compounds of the general formula (V) ##STR9## in which R¹, R², R³and R⁴ have the meaning indicated,

in inert solvents, if appropriate in the presence of a base.

Suitable solvents for the process are the customary organic solventswhich do change under the reaction conditions. These preferably includeethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether, or hydrocarbons such as benzene, toluene, xylene, hexane,cyclohexane or petroleum fractions, or halogenohydrocarbons such asdichloromethane, trichloromethane, tetrachloromethane, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, triethylamine,pyridine, dimethyl sulphoxide, dimethylformamide,hexamethylphosphoramide, acetonitrile, acetone or nitromethane. It isalso possible to use mixtures of the solvents mentioned.Dimethylformamide and tetrahydrofuran are preferred.

The bases employed for the process according to the invention can ingeneral be inorganic or organic bases. These preferably include alkalimetal hydroxides, for example, sodium hydroxide or potassium hydroxide,alkaline earth metal hydroxides, for example, barium hydroxide, alkalimetal carbonates such as sodium carbonate or potassium carbonate,alkaline earth metal carbonates such as calcium carbonate, or alkalimetal alkoxides such as sodium or potassium methoxide, sodium orpotassium ethoxide or potassium tert-butoxide, or organic amines(trialkyl(C₁ -C₆)amines) such as triethylamine, or heterocycles such as1,4-diazabicyclo 2.2.2!octane (DABCO), 1,8-diazabicyclo5.4.0!undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine .or morpholine. It is also possible to employ alkali metals such assodium or their hydrides such as sodium hydride as bases. Sodiumhydride, potassium carbonate, triethylamine, pyridine and potassiumtert-butoxide, DBU or DABCO are preferred.

In general, the base is employed in an amount from 0.05 mol to 10 mol,preferably from 1 mol to 2 mol, relative to 1 mol of the compound of theformula (IV).

The process according to the invention is in general carried out in atemperature range from -30° C. to +100° C., preferably from -10° C. to+60° C.

The process according to the invention is in general carried out atnormal pressure. However, it is also possible to carry out the processat elevated pressure or at reduced pressure (e.g. in a range from 0.5 to5 bar).

The compounds of the general formula (III) are known per se.

The compounds of the general formula (IV) are known or can be preparedin analogy to known methods.

The compounds of the general formula (V) are known or can be prepared inanalogy to known methods.

The compounds of the general formula (I) according to the invention havean unforeseeable spectrum of pharmacological action.

They can be used as active compounds in medicamnents for the reductionof changes to vessel walls and for the treatment of coronary heartdisorders, cardiac insufficiency, brain power disorders, ischaemic braindisorders, apoplexy, circulatory disorders, disorders of themicrocirculation and thromboses.

Furthermore, the proliferation of smooth muscle cells plays a decisivepart in the occlusion of vessels. The compounds according to theinvention are suitable for inhibiting this proliferation and thuspreventing atherosclerotic processes.

The compunds according to the invention are distinguished by a loweringof the ApoB-100-associated lipoproteins (VLDL and its degradationproducts, e.g. LDL), of ApoB-100, of triglycerides and of cholesterol.They thus have useful, superior pharmacological properties in comparisonwith the prior art.

Surprisingly, the action of the compounds according to the inventionconsists first in a decrease or complete inhibition of the formationand/or the release of ApoB-100-associated lipoproteins from liver cells,which results in a lowering of the VLDL plasma level. This lowering ofVLDL must be accompanied by a lowering of the plasma level of ApoB-100,LDL, triglycerides and cholesterol; a number of the abovementioned riskfactors which are involved in vessel wall changes are thussimultaneously decreased.

The compounds according to the invention can therefore be employed, forthe prevention and treatment of atherosclerosis, obesity, pancreatitisand constipation.

I. Inhibition of the Release of ApoB-100-associated Lipoproteins

The test for detecting the inhibition of the release ofApoB-100-associated lipoproteins from liver cells was carried out invitro using cultured liver cells, preferably using cells of the humanline HepG2. These cells are cultured under standard conditions in mediumfor the culture of eukaryotic cells, preferably in RPMI 1640 with 10%foetal calf serum. HepG2 cells synthesize and secrete into the culturesupenatant ApoB-100-associated lipoprotein particles which in principleare built up in a similar manner to the VLDL and LDL particles which areto be found in the plasma.

These particles can be detected using an immunoassay for human LDL. Thisimmunoassay is carried out using antibodies which have been inducedagainst human LDL in rabbits under standard conditions. The anti-LDLantibodies (rabbit anti-LDL Ab) were purified by affinity chromatagraphyon an immunosorbent using human LDL. These purified rabbit anti-LDL Abare adsorbed on the surface of plastic. Expediently, this adsorption iscarried out on the plastic surface of microtitre plates having 96 wells,preferably on MaxiSorp plates. If ApoB-100-associated particles arepresent in the supernatant of Hep-G2 cells, they can be bound to theinsolubilized rabbit anti-LDL Ab, and an immune complex results which isbound to the plastic surface. Unbound proteins are removed by washing.The immune complex located on the plastic surface is detected usingmonoclonal antibodies which have been induced against human LDL andpurified according to standard conditions. These antibodies wereconjugated with the enzyme peroxidase. Peroxidase converts thecolourless substrate TMB into a coloured product in the presence of H₂O₂. After acidification of the reaction mixture with H₂ SO₄, thespecific light absorption at 450 nm is determined, which is a measure ofthe amount of ApoB-100-associated particles which have been secretedinto the culture supernatant by the HepG2 cells.

Surprisingly, the compounds according to the invention inhibit therelease of the ApoB-100-associated particles. The IC₅₀ value indicatesat which substance concentration the light absorption is inhibited by50% in comparison with the control (solvent control without substance).

    ______________________________________                                        Ex. No.      IC.sub.50  10.sup.9 mol/l!                                       ______________________________________                                        1            28                                                               5            1.1                                                              31           170                                                              50           29                                                               ______________________________________                                    

2. Determination of the VLDL Secretion in vivo in the Hamster

The effect of the test substances on VLDL secretion in vivo isinvestigated in the hamster. To do this, golden hamsters areanaesthetized with Ketaset (83 mg/kg s.c.) and Nembutal (50 mg/kg i.p.)after premedication with atriopine (83 mg/kg s.c.). When the animalshave become reflex-free, the jugular vein is exposed and cannulated.0.25 ml/kg of a 20% strength solution of Triton WR-1339 in physiologicalsaline solution is then administered. This detergent inhibits thelipoprotein lipase and thus leads to a rise in the triglyceride level asa result of a lack of catabolism of secreted VLDL particles. Thistriglyceride rise can be used as a measure of the VLDL secretion rate.

Blood is taken from the animals before and also one and two hours afteradministration of the detergent by puncture of the retroorbital venousplexus. The blood is incubated for two hours at room temperature, andthen overnight at 4° C., in order to end clotting completely. It is thencentrifuged at 10,000 g for 5 minutes. The triglyceride concentration inthe serum thus obtained is determined with the aid of a modifiedcommercially available enzyme test (Merckotest® triglyceride No. 14354).100 μl of serum are treated with 100 μl of test reagent in 96-holeplates and incubated at room temperature for 10 minutes. The opticaldensity is then determined at a wavelength of 492 nM in an automaticplate-reading apparatus (SLT Spectra). Serum samples having anexcessively high triglyceride concentration are diluted withphysiological saline solution. The triglyceride concentration containedin the samples is determined with the aid of a standard curve measuredin parallel. In this model, test substances are administeredintravenously either immediately before administration of the detergentor orally or subcutaneously before initiation of anaesthesia.

    ______________________________________                                        Ex. No.      ED.sub.50  mg/kg! p.o.                                           ______________________________________                                        2            10-15                                                            5            3-6                                                              7            10-20                                                            ______________________________________                                    

3. Inhibition of Intestinal Triglyceride Absorption in vivo (Rats)

The substances which are to be investigated for their triglycerideabsorption-inhibiting action in vivo are administered orally to maleWistar rats having a body weight of between 170 and 230 g. For thispurpose, the animals are divided into groups of 6 animals 18 hoursbefore substance administration and food is then withdrawn from them.Drinking water is available to the animals ad libitum. The animals ofthe control groups receive an aqueous tragacanth suspension or atragacanth suspension which contains olive oil. The tragacanth-olive oilsuspension is prepared using an Ultra-Turrax. The substances to beinvestigated are suspended in an appropriate tragacanth-olive oilsuspension likewise using the Ultra-Turrax, directly before substanceadministration.

To determine the basal serum triglyceride content, blood is taken fromeach rat by puncture of the retroorbital venous plexus before stomachtube application. The tragacanth suspension, the tragacanth-olive oilsuspensions without substance (control animals) or the substancessuspended in an appropriate tragacanth-olive oil suspension are thenadministered to the fasting animals using a stomach tube. Further takingof blood to determine the postprandial serum triglyceride rise iscaxried out, as a rule, 1, 2 and 3 hours after stomach tube application.

The blood samples are centrifuged and, after recovering the serum, thetriglycerides are determined photometrically using an EPOS analyzer 5060(Eppendorf Geratebau, Netheler & Hinz GmbH, Hamburg). The determinationof the triglycerides is carried out completely enzymatically using astandard commercial UV test.

The postprandial serum triglyceride rise is determined by subtraction ofthe triglyceride preliminary value of each animals from itscorresponding postprandial triglyceride concentrations (1, 2 and 3 hoursafter administration).

The differences (in mmol/l) at each point in time (1, 2 and 3 hours) areaveraged in the groups, and the mean values of the serum triglyceriderise (ΔTG) of the substance-treated animals is compared with the animalswhich only received the tragacanth-oil suspension.

The serum triglyceride course of the control animals which only receivedtragacanth is also calculated. The substance effect at each point intime (1, 2 and 3 hours) is determined as follows and indicated in Δ% ofthe oil-loaded control. ##EQU1##

Effect of 10 mg of test substance/kg of body weight p.o. on thetriglyceride rise (Δ%) 2 h afer a triglyceride loading in the serum offasting rats. The serum triglyceride rise of fat-loaded control animalsrelative to the serum triglyceride level of tragacanth control animalscormponds to 100% n=6 animals per group.

    ______________________________________                                                           Serum triglyceride rise                                                       in % (2 h pp)                                              ______________________________________                                        Triglyceride loading 100                                                      Tragacanth control   0                                                        Substance 10 mg/kg of body weight p.o.                                        Ex No. 10            34                                                       Ex. No. 66           67                                                       Ex. No. 54           54                                                       Ex. No. 71           18                                                       Ex. No. 5            -16                                                      Ex. No. 20           35                                                       ______________________________________                                    

Statistical evaluation is carried out using Student's t test afterpreliminary checking of the variances for homogeneity.

Substances which at one point in time statistically significantly(p<0.05) decrease the postprandial serum triglyceride rise by at least30% compared with the untreated control group are regarded aspharmacolocally active.

4. Inhibition of VLDL Secretion in vivo (Rats)

The action of the test substances on VLDL secretion is likewiseinvestigated in the rat. To do this, 500 mg/kg of body weight (2.5mg/kg) of Triton WR-1339, dissolved in physiological saline solution, isadministered intravenously into the tail vein of rats. Triton WR-1339inhibits lipoprotein lipase and thus leads to an increase in thetriglyceride and cholesterol level by inhibition of the VLDL catabolism.These rises can be used as a measure of the VLDL secretion rate.

Blood is taken from the animals by puncture of the retroorbital venousplexus before and also one and two hours after administration of thedetergent. The blood is incubated at room temperature for 1 h forcloning and the serum is obtained by centrifugation at 10,000 g for 20s. The triglycerides are then photometrically determined by means of astandard commercial coupled enzyme test (Sigma Diagnostics®, No. 339) ata wavelength of 540 nm. Measurement is carried out with the aid of alikewise coupled enzyme test (Boehring Mannheim ®, No. 1442350) at awavelength of 546 nm. Samples with triglyceride or cholesterolconcentrations which exceed the measuring range of the methods arediluted with physiological saline solution. The determination of therespective serum concentrations is carried out with the aid of standardseries measured in parallel. Test substances are administered orally,intravenously or subcutaneously immediately after the Triton injection.

The invention additionally relates to the combination ofcycloalkano-indole and -azaindole derivatives of the general formula (I)with glucosidase and/or amylase inhibitor for the treatment of familialhyperlipidaemia, obesity (adiposity) and diabetes mellitus. Glucosidaseand/or amylase inhibitors in the context of the invention are, forexample, acarbose, adiposine, voglibase, miglitol, emiglitate, MDL25637, camiglibase (MDL 73945), tendamistat, AI-3688, trestatin,pradimilin-Q and salbostatin.

Combination of acarbose, miglitol, emiglitate or voglibase with one ofthe abovementioned compounds of the general formula (I) according to theinvention is preferred.

The new active compounds can be converted in a knovm manner into thecustomary formulations, such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, non-toxic, pharmaceutically suitable excipients or solvents. Inthis case, the therapeutically active compound should in each case bepresent in a concentration of approximately 0.5 to 90% by weight of thetotal mixture, i.e. in amounts which are sufficient in order to achievethe dosage range indicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, if appropriate usingemulsifiers and/or dispersants, it optionally being possible, e.g. inthe case of the use of water as a diluent, to use organic solvents asauxiliary solvents.

Administration is carried out in a customary manner, preferably orallyor parenterally, in particular perlingually or intravenously.

In the case of parenteral administration, solutions of the activecompound can be employed using suitable liquid vehicles.

In general, it has proved advantageous in the case of intravenousadminstration to administer amounts of approximately 0.001 to 1 mg/kg ofbody weight, preferably approximately 0.01 to 0.5 mg/kg of body weight,to achieve effective results, and in the case of oral administration thedose is approximately 0.01 to 20 mg/kg of body weight preferably 0.1 to10 mg/kg of body weight.

In spite of this, it may optionally be necessary to depart from theamounts mentioned, namely depending on the body weight or on the type ofadministration route, on individual behaviour towards the medicament,the manner of its formulation and the time or interval at whichadministration takes place. Thus, in some cases it may be adequate tomanage with less than the abovementioned minimum amount, while in othercases the upper limit mentioned must be exceeded. In the case of theadministration of larger amounts, it may be advisable to divide theseinto several individual doses over the course of the day.

Definition of the Isomer Types:

4 dia=mixture of the four possible diastereomers in the case of twocentres of asymmetry in the molecule

dia A=diastereomer having the large R_(f) value

dia B=diastereomer having the smaller R_(f) value

ent=enantiomer

2 ent dia=mixture of two enantiomerically pure diastereomers

ent dia A=enantiomerically pure diastereomer having the larger R_(f)value

ent dia B=enantiomerically pure diastereomer having the smaller R_(f)value

R=R enantiomer

rac=racemate

rac dia A=racermic diastereomer having the larger R_(f) value

rac dia B=racemic diastereomer having the smaller R_(f) value

S=S enantiomer

Abbreviations Used:

Ac=acetyl

Bn=benzyl

Bz=benzoyl

iB=isobutyl

nBu=normal butyl

sBu=secondary butyl

tBu=tertiary butyl

DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone

cDec=cyclo-decyl

DMF=N,N-dimethylformamide

DMSO=dimethyl sulphoxide

cDodec=cyclo-dodecyl

Et=ethyl

cHept=cyclo-heptyl

cHex=cyclo-hexyl

HOBT=1-hydroxy- 1H-benzotriazole

Me=methyl

Mes=mesyl

cNon=cyclo-nonyl

cOct=cyclo-octyl

cPent=cyclo-pentyl

nPent=normal pentyl

Ph=phenyl

cPr=cyclo-propyl

nPr=normal propyl

iPr=isopropyl

THF=tetrahydrofuran

TMS=tetramethylsilane

pTol=para-tolyl

pTos=para-tosyl

cUndec=cyclo-undecyl

    ______________________________________                                        Solvent                    Symbol                                             ______________________________________                                        Dichloromethane:methanol = 20:1                                                                          A                                                  Dichloromethane:methanol = 50:1                                                                          B                                                  Dichloromethane:ethanol = 20:1                                                                           C                                                  Dichloromethane:ethanol = 50:1                                                                           D                                                  Petroleum ether:ethyl acetate = 1:1                                                                      E                                                  Dicloromethane:methanol:acetic acid = 90:10:2                                                            F                                                  Petroleum ether:ethyl acetate = 2:1                                                                      G                                                  Petroleum ether:ethyl acetate = 10:1                                                                     H                                                  Toluene                                                                       Toluene:ethyl acetate = 1:1                                                                              K                                                  Petroleum ether:ethyl acetate = 5:1                                                                      L                                                  Dichloromethane            M                                                  Petroleum ether:ethyl acetate = 20:1                                                                     N                                                  Dichloromethane:methanol 10:1                                                                            O                                                  Cyclohexane:ethyl acetate = 1:1                                                                          P                                                  Toluene:ethyl acetate = 9:1                                                                              Q                                                  Toluene:ethyl acetate = 8:1                                                                              R                                                  Petroleum ether:ethyl acetate = 1:2                                                                      S                                                  Dichloromethane:ethanol = 5:1                                                                            T                                                  Dichloromethane:ethanol = 10:1                                                                           U                                                  ______________________________________                                    

Preparation Procedure for the TLC Mobile Phase BABA:

87.9 ml of an aqueous 0.06667 molar potassium dihydrogen phosphatesolution and 12.1 ml of an aqueous 0.06667 molar disodium hydrogenphosphate solution are mixed. 60 ml of the solution prepared in this wayare shaken with 200 ml of n-butyl acetate, 36 ml of n-butanol and 100 mlof glacial acetic acid and the aqueous phase is removed. The organicphase is the mobile phase BABA.

Starting Compounds EXAMPLE I 1-Allyloxy-2-chloromethylbenzene ##STR10##

11.5 g (70 mmol) of 1-allyloxy-2-hydroxymethyl-benzene are treated with11.6 ml (84 mmol) of triethylamine at 0° C. in 110 ml of dichloromethaneand then slowly reacted with 5.4 ml (70 mmol) of methanesulphonylchloride. After 4 hours, the mixture is extracted several times withwater, and the organic phase is dried over magnesium sulphate andevaporated. Residual solvent is removed in a high vacuum.

Yield: 8.5 g

R_(f) =0.23 (dichloromethane : ethanol=20:1)

EXAMPLE II (2-Allyloxy-benzyl)amine ##STR11##

3.0 g (16.4 mmol) of the compound from Example I are boiled under refluxfor 17 hours in 250 ml of a saturated methanolic ammonia solution. Thereaction mixture is evaporated in vacuo, the residue is taken up inmethanol and the mixture is evaporated again; this process is repeated afew times. The crude product is taken up in dichloromethane andextracted several times with water. The aqueous phase is evaporated to avery great extent, an oil being obtained which crystallizes on standing.

Yield: 0.454 g (crude)

The product is reacted further without further purification.

R_(f) =0.41 (mobile phase: BABA)

EXAMPLE III 6-Chloro-2,4-lutidine ##STR12##

For the preparation of the title compound US 36 32 807!, 600 g (4.91mol) of 6-amino-2,4-1utidine are dissolved in 2 l of methanol and thesolution is saturated with hydrogen chloride gas at about 0° C. 1.307 l(9.82 mol) of isopentyl nitrite are added dropwise (about 2.5 h) at anintemal temperature of below 10° C. and the mixture is in this way for15 h while warming to room temperature (about 25° C.). The solution islargely freed from the solvent in vacuo, mixed with 3 l ofdichloromethane and 1.5 l of water and adjusted to pH=9.5 while cooling(<20° C.) with concentrated aqueous ammonia solution. The separatedorganic phase is dried with sodium sulphate, first concentrated in vacuoon a rotary evaporator and then distilled through a Vigreux column:

Fraction 1) B.p.=47°-49° C. (12 mm Hg), 603 g

Fraction 2) B.p.=82°-85° C. (12 mm Hg), 612 g (about 88% crude)

R_(f) =0.39 (petroleum ether: ethyl acetate=10:1)

¹ H-NMR (CDCl₃ 200 MHz, TMS): δ=2.28 (S, 3H), 2.47 (S, 3H), 6.88 (S,1H), 6.96 (S, 1H) ppm.

The crude product, which may contain small amounts of6-methoxy-2,4-lutidine, is reacted further without further purification.

EXAMPLE IV 6-Hydrazino-2,4-lutidine (4,6-dimethyl-2-hydrazino-pyridine)##STR13##

580 g (4.10 mol) of the compound from Example III are dissolved in 800ml of diethylene glycol and the solution is stirred with 1050 ml ofhydrazine hydrate for 48 h at a bath temperature of about 140° C. Thecooled mixture is poured into 4.5 l of ether and 4.5 l of water and theorganic phase is extracted twice with 2.3 l of dichloromethane eachtime. The combined organic phases are dried with sodium sulphate andevaporated in vacuo. 784 g of solvent-containing crude product areobtained, which is reacted further without working up.

R_(f) ≈0.37 (dichlommethane:methanol=10:1)

¹ H-NMR (d₆ -DMSO, 250 MHz, TMS): δ=2.13 (S, 3H), 2.22 (S, 3H), 4.02 (S,2H), 6.26 (S, 1H), 6.35 (S, 1H), 7.11 (S, 1H) ppm.

EXAMPLE V 2-Hydrazino-4-picoline (2-hydrazino-4-methylpyridine)##STR14##

In analogy to the procedure of Example IV, 2-hydrazino-4-picoline isprepared from 2-chloro-4-picoline.

R_(f) =0.06 (dichloromethane:methanol=10:1)

EXAMPLE VI 2,4-Dimethyl-5,6,7,8-tetrahydro-α-carboline ##STR15##

78 g (at most 0.49 mol) of crude compound from Example IV are reactedwith 59 ml (0.56 mol) of cyclohexanone at room temperature (about 25°C.), whereon the internal tenmperature rises. After 2 h, the startingmaterial has disappeared (TLC checking dichloromethane:methanol=10:1).The mixture is taken up in 40 ml of diethylene glycol and reacted underreflux, constituents having a boiling point lower than the solvent (e.g.water of reaction and excess cyclohexanone) being removed bydistillation (water separator). After 3 h, the intermediate hydrazonehas disappeared (TLC checking petroleum ether: ethyl acetate=1:1); thereaction mixture is cooled to room temperature and stirred with acetone.The precipitate obtained is filtered off with suction, washed withacetone and dried in vacuo (34.4 g). The largely solvent-free motherliquors are again treated with acetone, a further 9.3 g of product beingobtained (total yield over three stages: 43.7 g/0.22 mol/47%).

M.p.: 248° C. (uncorrected)

R_(f) =0.41 (dichloromethane:methanol=20:1)

¹ H-NMR (d₆ -DMSO, 200 MHz, TMS): δ=1.78 (M, 4H), 2.40 (S, 3H), 2.48 (S,3H), 2.64 (M, 2H), 2.82 (M, 2H), 6.57 (S, 1H), 10.84 (S, 1H) ppm.

The compounds of Table I are prepared analogously to the procedure ofExample VI.

                                      TABLE I                                     __________________________________________________________________________                                 Starting material                                No. Ex.                R.sub.f (solvent)                                                                   (hydrazine*)                                     __________________________________________________________________________    VII                                                                                ##STR16##         0.59 (A)                                                                            Ex. No. IV                                       VIII                                                                               ##STR17##         0.36 (E)                                                                            Ex. No. IV                                       IX                                                                                 ##STR18##         0.45 (G)                                                    ##STR19##         0.46 (E)                                               XI                                                                                 ##STR20##         0.06 (L)                                               XII                                                                                ##STR21##         0.41 (E)                                               XIII                                                                               ##STR22##         0.40 (E)                                               XIV                                                                                ##STR23##         0.59 (O)                                               XV                                                                                 ##STR24##         0.34 (E)                                               XVI                                                                                ##STR25##         0.42 (E)                                               XVII                                                                               ##STR26##         0.59 (G)                                               XVIII                                                                              ##STR27##         0.85 (G)                                               __________________________________________________________________________

EXAMPLE XIX 2,4-Dimethyl-α-carboline ##STR28##

100 g (499 mmol) of the compound from Example VI are reacted underreflux with 164 ml (1 mol) of diethyl furnarate on 52 g of palladium (5%on carbon) in 700 ml of diethylene glycol. A small amount of ethanoldistils off at the high internal temperature (if desired use a waterseparator). After about 8 h, the starting material has disappeared (TLCchecking petroleum ether:ethyl acetate=1:1, detection in an iodinechamber). The cooled mixture is treated with 3 l of acetone, boiled,filtered off hot with suction through a clarifying filter (Seitz) andwashed with 1 l of hot acetone. On cooling a precipitate is obtainedwhich yields 58.3 g of product after filtering with suction, rinsingwith cold acetone and drying in vacuo. The mother liquor is largelyfreed from acetone in vacuo, the precipitate which is deposited beingworked up as above (9.4 g). The filtrate is again freed from acetone;after addition of n-pentane, product precipitates a further time (3.1g/working up see above); total yield 72%.

M.p. 220°-221° C. (uncorrected) R_(f) =0.47 (petroleum ether:ethylacetate=1:1) ¹ H-NMR (d₆ -DMSO, 200 MHz, TMS): δ=2.54 (S, 3H), 2.75 (S,3H), 6.89 (S, 1H), 7.20 (M, 1H), 7.40 (M, 1H), 7.48 (DD, 1H), 8.05 (DD,1H), 11.61 (S, 1H)

EXAMPLE XX tert-Butyl 4-methylphenyl-acetate ##STR29##

450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol)of tert-butanol and 90 g (0.74 mol) of 4-(N,N-dimethylamino)pyridine aredissolved in 2 l of dichloromethane. After addition of 680 g (3.3 mol ofdicyclohexylcarbodiimide, dissolved in 400 ml of dichloromethane, themixture is stirred at 25° C. for 20 h, the precipitated urea is filteredoff with suction and washed with 200 ml of dichloromethane, and theorganic phase is washed twice each with 500 ml of 2M hydrochloric acidand water. The organic phase is concentrated and distilled.

Yield: 408 g (66% of theory) Boiling point: 73°-78° C./0.2 mm

EXAMPLE XXI tert-Butyl 2-Cyclopentyl-2-(4-methylphenyl)acetate ##STR30##

33.5 g (0.3 mol of potassium tert-butoxide are initially introduced into100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) of the compoundfrom Example XX in 250 ml of anhydrous DMF are added dropwise. Themixture is stirred at 0° C. for 30 min and 32.2 ml (0.3 mol) ofcyclopentyl bromide in 150 ml of anhydrous DMF are added dropwise at5°-15° C. and the mixture is stirred at 25° C. for 20 h. Afterconcentrating, the residue is partitioned between water and diethylether, and the ether phase is dried over sodium sulphate andconcentrated. The product crystallizes out.

Yield: 67 g (97.5% of theory)

Solidification point: 51°-53° C.

The compounds of Table II are prepared in analogy to the procedure ofExample XXI:

                  TABLE II                                                        ______________________________________                                         ##STR31##                                                                    Ex. No.  D       R.sup.19                                                                              R.sub.f (solvent)                                                                      Starting material*                          ______________________________________                                        XXII     cHex    tBu     0.71 (I) Ex. No. XX                                  XXIII    cHept   tBu     0.32 (I) Ex. No. XX                                  XXIV     iPr     CH.sub.3                                                                              0.86 (Q) sigma                                       XXV      iBu     tBu     0.84 (R) Ex. No. XX                                  XXVI     cPent   CH.sub.3                                                                              0.59 (H) sigma                                       XXVII    cHept   CH.sub.3                                                                              0.57 (I) sigma                                       ______________________________________                                    

EXAMPLE XXVIII tert-Butyl 2-(4-bromomethyl-phenyl)-2-cyclopentyl-acetate##STR32##

27.4 g (0.1 mol) of the compound from Example XXI are dissolved in 200ml of tetrachloromethane and the solution is heated to boiling. Afteraddition of 0.82 g of azobisisobutyronitrile, 18.7 g (0.105 mol) ofN-bromosuccinimide are added in portions and the mixture is thenrefluxed for 1 h, cooled to 0° C. and succinimide is filtered off. Afterconcentrating the filtrate the product precipitates. It is washed withpetroleum ether (40/60) and dried.

Yield: 20 g (57% of theory)

M.p.: 73°-76° C.

The compounds of Table III are prepared analogously to the procedure ofExample XXVIII:

                  TABLE III                                                       ______________________________________                                         ##STR33##                                                                                                      Starting material*                          Ex. No.  D       R.sup.19                                                                              R.sub.f (solvent)                                                                      (Syn. from Ex. No.)                         ______________________________________                                        XXIX     cHex    tBu     0.58 (H) Ex. No. XXII                                XXX      cHept   tBu     0.84 (M) Ex. No. XXIII                               XXXI     iPr     CH.sub.3                                                                              0.78 (M) Ex. No. XXIV                                XXXII    iBu     tBu     0.86 (M) Ex. No. XXV                                 XXXIII   cPent   CH.sub.3                                                                              0.63 (H) Ex No. XXVI                                 XXXIV    cHept   CH.sub.3                                                                              0.59 (I) Ex. No. XXVII                               ______________________________________                                    

EXAMPLE XXXV tert-Butyl 2(R,S)-2-cyclopentyl-2-4-(2,4-dimethyl-α-carbolin-9-yl)methyl!phenyl-acetate ##STR34##

73.6 g (375 mmol) of the compound from Example XIX are reacted at 25° C.for 30 min with 42.13 g (375 mmol) of potassium tert-butoxide in 700 mlof anhydrous N,N-dimethylformamide and the mixture is then treated with161.7 g (375 mmol) of the compound from Example XXVIII, dissolved in 680ml of anhydrous N,N-dimethylfonnamide. The reaction is complete after 1h (TLC checking petroleum ether:ethyl acetate=10:1). For working up, 2 lof buffer solution (pH=4/Merck) and 2 l of water are added, theprecipitate which is deposited is filtered off, washed with water andagain filtered off rapidly. The moderately damp solid is then stirredsuccessively with petroleum ether and methanol and filtered off withsuction. Vacuum drying over phosphorus pentoxide yields 139.8 g (298mmol/79%) of product.

M.p.: 160°-161° C. (uncorrected).

R_(f) =0.39 (petroleum ether:ethyl acetate=10:1)

¹ H-NMR (CDCl₃, 250 MHz, TMS): δ=0.91 (M, 1H), 1.18-1.68 (M, 6H), 1.87(M, 1H), 1.47 (S, 9H), 2.42 (M, 1H), 2.66 (S, 3H), 2.83 (S, 3H), 3.09(D, 1H), 5.67 (S, 2H), 6.88 (S, 1H), 7.13-7.41 (M, 7H), 8.09 (D, 1H)ppm.

The compounds of Tables IV and V are prepared analogously to theprocedure of Example XXXV:

                                      TABLE IV                                    __________________________________________________________________________     ##STR35##                                                                                                         Starting material                        Ex. No.                                                                            Z                   D  R.sub.f (solvent)                                                                      (Syn. from Ex. No.)                      __________________________________________________________________________    XXXVI                                                                               ##STR36##          cPent                                                                            0.28 (H) Benzyl bromide: Ex. No. XXVII                                                 Heterocycle: Ex. No. VI                  XXXVII                                                                              ##STR37##          cHept                                                                            0.47 (H) Benzyl bromide: Ex. No.                                                       XXX Heterocycle: Ex. No. XIX             XXVIII                                                                              ##STR38##          cHept                                                                            0.54 (L) Benzyl bromide: Ex. No.                                                       XXX Heterocycle: Ex. No. VII             XXXIX                                                                               ##STR39##          cHept                                                                            0.27 (H) Benzyl bromide: Ex. No.                                                       XXX Heterocycle: Ex. No. VI              XL                                                                                  ##STR40##          cPent                                                                            0.59 (D) Benzyl bromide: Ex. No. XXVIII                                                Heterocycle: Ex No. VIII                 XLI                                                                                 ##STR41##          cHept                                                                            0.29 (H) Benzyl bromide: Ex. No.                                                       XXX Heterocycle: Ex. No. VIII            XLII                                                                                ##STR42##          cPent                                                                            0.70 (M) Benzyl bromide: Ex. No. XXVIII                                                Heterocycle: Ex. No. IX                  XLIII                                                                               ##STR43##          cHept                                                                            0.36 (H) Benzyl bromide: Ex. No.                                                       XXX Hetrocycle: Ex. No. IX               XLIV                                                                                ##STR44##          cHept                                                                            0.48 (L) Benzyl bromide: Ex. No. XXX              XLV                                                                                 ##STR45##          cPent                                                                            0.49 (C) Benzyl bromide: Ex. No. XXVIII           XLVI                                                                                ##STR46##          cPent                                                                            0.51 (C) Benzyl bromide: Ex. No. XXVIII           XLVII                                                                               ##STR47##          cPent                                                                            0.54 (C) Benzyl bromide: Ex. No. XXVIII           XLVIII                                                                              ##STR48##          cPent                                                                            0.37 (N) Benzyl bromide: Ex. No. XXVIII                                                Heterocycle: Ex. No. XI                  IL                                                                                  ##STR49##          cHept                                                                            0.56 (H) Benzyl bromide: Ex. No.                                                       XXX Heterocycle: Ex. No. XI                    ##STR50##          cPent                                                                            0.57 (C) Benzyl bromide: Ex. No. XXVIII           LI                                                                                  ##STR51##          cHex                                                                             0.35 (H) Benzyl bromide: Ex. No. XXIX                                                  Hetrocycle: Ex. No. VI                   LII                                                                                 ##STR52##          cHex                                                                             0.57 (B) Benzyl bromide: Ex. No. XXIX                                                  Heterocycle: Ex. No. XIX                 LII                                                                                 ##STR53##          cPent                                                                            M.p. = 189-190° C.                                                              Benzyl bromide: Ex. No. XXVIII                                                Heterocycle: a) C. Herdeis et al.,                                            Heterocycles 22, 2277 (1984).            LIV                                                                                 ##STR54##          iBu                                                                              0.49 (M) M.p.: 142° C. MS                                              (CI/NH.sub.3) 457 (100%)                                                               Benzyl bromide: c) Ex. No. XXXII                                              Heterocycle: c) Ex. No.                  __________________________________________________________________________                                         XIX                                  

                                      TABLE V                                     __________________________________________________________________________     ##STR55##                                                                                             R.sub.f (solvent)                                                                    Starting material                             Ex. No.                                                                           Z                 D  MS/M.p.                                                                              (Syn. from Ex. No.)                           __________________________________________________________________________    LV                                                                                 ##STR56##        iPr                                                                              0.39 (M) M.p. = 159° C. MS (Cl/NH.sub.3):                              01 (100%)                                                                            Benzyl bromide: Ex. No. XXXI Heterocycle:                                     Ex. No. XIX                                   LVI                                                                                ##STR57##        cPent                                                                            0.76 (B)                                                                             Benzyl bromide: Ex. No.                                                       XXXIII Heterocycle: Ex. No. XIX               LVII                                                                               ##STR58##        cHept                                                                            0.26 (H)                                                                             Benzyl bromide: Ex. No.                                                       XXXIV Heterocycle: Ex. No. VI                 LVIII                                                                              ##STR59##        cHept                                                                            0.64 (K)                                                                             Benzyl bromide: Ex. No. XXXIV                 LIX                                                                                ##STR60##        cHept                                                                            0.29 (H)                                                                             Benzyl bromide: Ex. No.                                                       XXXIV Heterocycle: Ex. No. X                  LX                                                                                 ##STR61##        cHept                                                                            0.30 (H)                                                                             Benzyl bromide: Ex. No.                                                       XXXIV Heterocycle: Ex. No.                    __________________________________________________________________________                                    XIX                                       

EXAMPLE LXI 2-(R,S)-2-Cyclopentyl-2-4-(2,4-dimethyl-α-carbolin-9-yl)methyl!phenyl-acetic acid hydrochloride##STR62##

139.8 g (298 mmol) of the compound from Example XXXV are dissolved in 1l of 1,4-dioxane and the solution is stirred at 70° C. for 3 h with 240ml of concentrated hydrochloric acid (37% strength). After reaction iscomplete (TLC checking petroleum ether:ethyl acetate=10:1), the mixtureis cooled to about 15° C. and then poured in portions into 5 l of water.The pH is adjusted to 2.8 using 2M aqueous sodium hydroxide solution,and the precipitate obtained is filtered off with suction through apaper filter and washed with water until the washing water has a pH>4.The rapidly filtered off solid is stirred with 1 l of petroleum ether(boiling range 60°-80° C.), filtered off with suction again and driedover phosphorus pentoxide in vacuo.

Yield: 130.3 g (290 mmol/97%)

M.p.: 260°-262° C. (uncorrected)

R_(f) =0.51 (dichloromethane:ethanol=20:1)

¹ H-NMR (d₆ -DMSO, 200 MHz, TMS): δ=0.88 (M, 1H), 1.09-1.67 (M, 6H),1.79 (M, 1H), 2.38 (M, 1H), 2.68 (S, 3H), 2.84 (S, 3H), 3.16 (D, 1H),4.7-5.9 (1H) 5.80 (S, 2H), 7.12-7.26 (M, 5H), 7.32 (M, 1H), 7.49 (M,1H), 7.59 (D, 1H), 8.17 (D, 1H) ppm.

The compounds of Table VI are prepared analogously to the procedure ofExample LXI:

                                      TABLE VI                                    __________________________________________________________________________     ##STR63##                                                                                                         Starting material                        Ex. No.                                                                            Z                   D  R.sub.f (solvent)                                                                      (Syn. from Ex. No.)                      __________________________________________________________________________    LXII                                                                                ##STR64##          cPent                                                                            0.37 (A) Ex. No. XXXVI                            LXIII                                                                               ##STR65##          cHept                                                                            0.23 (G) Ex. No. XXXVII                           LXIV                                                                                ##STR66##          cHept                                                                            0.30 (E) Ex. No. XXXVIII                          LXV                                                                                 ##STR67##          cHept                                                                            0.27 (D) Ex. No. XXXIX                            LXVI                                                                                ##STR68##          cPent                                                                            0.37 (C) Ex. No. XL                               LXVII                                                                               ##STR69##          cHept                                                                            0.15 (C) Ex. No. XLI                              LXVIII                                                                              ##STR70##          cPent                                                                            0.43 (A) Ex. No. XLII                             LXIX                                                                                ##STR71##          cHept                                                                            0.27 (C) Ex. No. XLIII                            LXX                                                                                 ##STR72##          cHept                                                                            0.17 (E) Ex. No. XLIV                             LXXI                                                                                ##STR73##          cPent                                                                            0.07 (C) Ex. No. XLV                              LXXII                                                                               ##STR74##          cPent                                                                            0.26 (C) Ex. No. XLVI                             LXXIII                                                                              ##STR75##          cPent                                                                            0.39 (C) Ex. No. XLVII                            LXXIV                                                                               ##STR76##          cPent                                                                            0.46 (C) Ex. No. XLVIII                           LXXV                                                                                ##STR77##          cHept                                                                            0.68 (E) Ex. No. IL                               LXXVI                                                                               ##STR78##          cPent                                                                            0.44 (C) Ex. No. L                                LXXVII                                                                              ##STR79##          cHex                                                                             0.44 (C) Ex. No. LI                               LXXVIII                                                                             ##STR80##          cHex                                                                             0.55 (C) Ex. No. LII                              LXXIX                                                                               ##STR81##          cPent                                                                            M.p. = 204-205° C.                                                              Ex. No. LIII                             LXXX                                                                                ##STR82##          iBu                                                                              0.36 (A) M.p.: 156° C. MS (FAB): 401                                   (100%) 154 (90%)                                                                       Ex. No. LIV                              __________________________________________________________________________

EXAMPLE LXXXI 2-(R,S)-2-4-(2-Methyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl!-2-cylcoheptyl-aceticacid ##STR83##

1.5 g (3.37 mmol) of the compound from Example LIX are reacted with 20ml of 1M methanolic sodium hydroxide solution for 48 h. Water is addedthereto and the methanol component is evaporated. The alkaline aqueousphase is extracted several times with ether, freed from residues oforganic solvent in vacuo and adjusted to a pH of about 2 at 0°-5° C.using aqueous 1M hydrochloric acid. The precipitate which is depositedin this process is filtered off with suction, thoroughly washed withwater and dried over phosphorus pentoxide in a high vacuum.

Yield: 1.18 g

The reaction can be accelerated using potassium hydroxide instead ofsodium hydroxide and with addition of 1, 4, 7, 10, 13,16-hexaoxacyclooctadecane.

R_(f) =0.39 (petroleum ether:ethyl acetate=2:1)

The compounds of Table VII are prepared in analogy to the procedure ofExample LXXXI:

                                      TABLE VII                                   __________________________________________________________________________     ##STR84##                                                                                                R.sub.f (solvent)                                                                    Starting material                          Ex. No.                                                                            Z                 D  1 MS/M.p.                                                                              (Synthesis from Ex. No.)                   __________________________________________________________________________    LXXXII Method 1                                                                     ##STR85##        iPr                                                                              rac                                                                             0.28 (A) M.p. = 225° C. MS (FAB): 387                                  (100%) 154 (80%)                                                                     Ex. No. LV                                 LXXXIII                                                                             ##STR86##        cHept                                                                            rac                                                                             0.05 (L)                                                                             Ex. No. LVII                               LXXXIV                                                                              ##STR87##        cHept                                                                            rac                                                                             0.11 (K)                                                                             Ex. No. LVIII                              LXXXVI                                                                              ##STR88##        cHept                                                                            rac                                                                             0.23 (G)                                                                             Ex. No. LX                                 LXXXVI                                                                              ##STR89##        cPent                                                                            rac                                                                             0.51 (C)                                                                             Ex. No. LVI                                __________________________________________________________________________

EXAMPLE LXXXII can also be prepared by method 2 which follows:

2- 4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-(prop-2-yl)-aceticacid ##STR90##

1.11 g (2.77 mmol) of the compound from Example No. LV are boiled underreflux for 18 hours in 45 ml of methanol and 3 ml of 2M aqueous sodiumhydroxide solution. As the reaction is incomplete according to TLC(dichloromethane:methanol=20:1), 30 ml of tetrahydrofuran and a further3 ml of 2M aqueous sodium hydroxide solution are added, a clear solutionbeing obtained. After boiling under reflux for four hours, the reactionis complete (TLC, see above). The mixture is cooled, diluted with waterand neutralized with 2M aqueous hydrochloric acid. The precipitate whichis obtained in this process is filtered off with suction, washed withwater and dried over phosphorus pentoxide in vacuo.

Yield: 0.597 g

M.p.=225° C.

R_(f) =0.28 (dichloromethane:methanol=20:1)

The compounds of Table VIII are prepared analogously to the procedure ofEXAMPLE XXXV:

                                      TABLE VIII                                  __________________________________________________________________________     ##STR91##                                                                    Ex. No.                                                                             Z                  M.p. (°C.)                                                                  Starting material*                              __________________________________________________________________________    LXXXVII                                                                              ##STR92##         164-165                                              LXXXVIII                                                                             ##STR93##         201-202                                              __________________________________________________________________________     *Ex. No. XXVIII was employed as the benzyl bromide.                      

The compounds of Table IX are prepared analogously to the procedure ofExample LXI:

                                      TABLE IX                                    __________________________________________________________________________     ##STR94##                                                                                                 Starting material                                Ex. No.                                                                            Z                  M.p. (°C.)                                                                  from Ex. No.                                     __________________________________________________________________________    LXXXIX                                                                              ##STR95##         262-263                                                                            LXXXVII                                          XC                                                                                  ##STR96##         279-280                                                                            LXXXVIII                                         __________________________________________________________________________

EXAMPLE XCI 2-Hydrazino-5-trifluoromethylpyridine ##STR97##

In analogy to the procedure of Example No. IV,2-hydrazino-5-trifluommethylpyddine is prepared from2-chloro-5-trifluommethylpyridine.

R_(f) =0.37 (BABA)

EXAMPLE XCII 5-Oxo-5,6,7-tetrahydro-α-carboline ##STR98##

3.3 g (19.2 mmol) of 5,6,7,8-tetrahydro-α-carboline (Lit.: S. Okuda andM. M. Robinson, J. Am. Chem. Soc. 81, 740 (1959)) are initiallyintroduced into 43 ml of tetrahydrofuran while stirring at 0° C. and themixture is treated dropwise with a solution of 15.5 g (68.2 mmol) of DDQin 277 ml of tetrahydrofuran and 31 ml of water. The reaction mixture isstirred at 0° C. for 5 minutes and at 20° C. for 2 hours, then treatedwith a buffer of pH=10 (Merck) and extracted with diethyl ether. Theevaporated organic phase yields a crude product which is purified bychromatography (silica gel 60, Merck, first petroleum ether:ethylacetate=1:1, then dichlommethane methanol=20:1). The fractions thusobtained are precipitated by stirring with acetone, and the product isfiltered off with suction and freed from the solvent in vacuo.

Yield: 0.92 g

R_(f) =0.17 (petroleum ether:ethyl acetate=1:4).

The compounds of Table X are prepared analogously to the procedure ofExample VI:

                                      TABLE X                                     __________________________________________________________________________                          M.p. (°C.)                                                                         Starting material                           Ex. No.                                                                           Z                 R.sub.f (solvent)                                                                   MS (EI)                                                                             from Ex. No.                                __________________________________________________________________________    XCIII                                                                              ##STR99##        0.27 (E)    V                                           XCIV                                                                               ##STR100##       0.46 (G)                                                                            240 (52%) 212 (100%)                                                                XCI                                         __________________________________________________________________________

                                      TABLE XI                                    __________________________________________________________________________                          M.p. (°C.)                                                                         Starting material                           Ex. No.                                                                           Z                 R.sub.f (solvent)                                                                   MS (EI)                                                                             from Ex. No.                                __________________________________________________________________________    XCV                                                                                ##STR101##       0.39 (G)                                                                            250 (100%)                                                                          IX                                          XCVI                                                                               ##STR102##       0.45 (G)    X                                           XCVII                                                                              ##STR103##       0.48 (G)                                                                            236 (100%)                                                                          XCIV                                        XCVIII                                                                             ##STR104##       0.3 (E)     XCIII                                       __________________________________________________________________________

The compounds of Table XII are prepared analogously to the procedure ofExample XXXV:

                                      TABLE XII                                   __________________________________________________________________________     ##STR105##                                                                                            M.p.  °C.!                                                                   Starting material                              Ex. No.                                                                           Z                 D  R.sub.f (solvent)                                                                   from Ex. No.                                   __________________________________________________________________________    IC                                                                                 ##STR106##       cPent                                                                            0.73 (C)                                                                            Benzyl bromide: Ex. No. XXVIII                      ##STR107##       cPent                                                                            0.63 (H)                                                                            Benzyl bromide: Ex. No. XXVIII Heterocycle:                                    Ex. No. XCV                                   CI                                                                                 ##STR108##       cPent                                                                            0.27 (H)                                                                            Benzyl bromide: Ex. No. XXVIII Heterocycle:                                    Ex. No. XCVI                                  CII                                                                                ##STR109##       cPent                                                                            0.33 (H)                                                                            Benzyl bromide: Ex. No. XXVIII Heterocycle:                                    Ex. No. XCI                                   CIII                                                                               ##STR110##       cPent                                                                            0.41 (H)                                                                            Benzyl bromide: Ex. No. XXVIII Heterocycle:                                    Ex. No. XCVII                                 CIV                                                                                ##STR111##       cPent                                                                            0.18 (H)                                                                            Benzyl bromide: Ex. No. XXVIII Heterocycle:                                    Ex. No. XCVIII                                __________________________________________________________________________     *racemic                                                                 

The compounds of Table XIII are prepared analogously to the procedure ofExample LXI:

                                      TABLE XIII                                  __________________________________________________________________________     ##STR112##                                                                                            M.p.  °C.!                                                                   Starting material                              Ex. No.                                                                           Z                 D  R.sub.f (solvent)                                                                   from Ex. No.                                   __________________________________________________________________________    CV                                                                                 ##STR113##       cPent                                                                            0.27 (C)                                                                            IC                                             CVI                                                                                ##STR114##       cPent                                                                            0.49 (C)                                                                            C                                              CVII                                                                               ##STR115##       cPent                                                                            0.38 (C)                                                                            CI                                             CVIII                                                                              ##STR116##       cPent                                                                            0.35 (C)                                                                            CII                                            CIX                                                                                ##STR117##       cPent                                                                            0.43 (C)                                                                            CIII                                           CX                                                                                 ##STR118##       cPent                                                                            0.29 (C)                                                                            CIV                                            __________________________________________________________________________     *racemic                                                                 

EXAMPLE NO. CXI 1-(R,S)-1-Phenyl-2-triphenylmethyloxy-ethanol ##STR119##

13 g (94 mmol) of 1-(R,S)-1-Phenyl-2-hydroxy-ethanol are reacted at 20°C. with 15.6 ml (113 mmol) of triethylamine and 23.6 g (84.6 mmol) oftriphenylmethyl 5 chloride in 200 ml of DMF. After 20 h, the mixture ispoured into buffer of pH=4 (Merck), the phases are separated, and theorganic phase is dried with magnesium sulphate and evaporated todryness. The crude product is purified by chromatography on silica gel60 (Merck/petroleum ether:ethyl acetate=20:1 later 10:1);

yield 27 g.

R_(f) =0.36 (petroleum ether:ethyl acetate=5:1)

EXAMPLE NO. CXII 6-Chloro-5-methyl-3-nitro-2-(2-oxo-cyclohexyl)-pyridine##STR120##

20 g (95.7 mmol) of 2,6-dichloro-5-methyl-3-nitro-pyridine are reactedwith 13.3 ml (95.7 mmol) of triethylamine and 14.5 g (95.7 mmol) offreshly distilled 1-pyrrolidino-cyclopentene at 20° C. in 200 ml of DMFunder argon as a protective gas. After the starting material hasdisappeared according to thin-layer chromatography (silica gel/petroleumether:ethyl acetate=4:1), 200 ml of 1M hydrochloric acid are added andthe mixture is diluted with about 600 ml of water. The precipitate whichis deposited is filtered off with suction, dried over phosphoruspentoxide in a high vacuum and purified by chromatography (silica gel60/Merck/petroleum ether:ethyl acetate=2:1).

R_(f) =0.69 (petroleum ether:ethyl acetate=4:1)

EXAMPLE NO. CXIII 2-Methyl-5,6,7,8-tetrahydro-δ-carboline ##STR121##

2.8 g (10.4 mmol) of the compound from Example CXII are reacted on 0.5 gof palladium (5%)/carbon in 30 ml of THF under a hydrogen pressure of 3bar for 18 h. The catalyst is then filtered off with suction and washedseveral times with methanol and dichloromethane. The flitrate isevaporated and dried in a high vacuum;

yield: 2.1 g

R_(f) =0.53 (dichloromethane:ethanol=5:1)

EXAMPLE NO. CXIV 3-Methyl-5,6,7,8-tetrahydro-α-carboline hydrochloride##STR122##

13.0 g (120.2 mmol) of 2-amino-5-methyl-pyridine are dissolved in 150 mlof ethanol and the solution is stirred with 60 ml of 2M hydrochloricacid, evaporated to dryness and finally dried over sodium hydroxide andphosphorus pentoxide in a high vacuum. The product thus obtained isboiled under reflux in a water separator with 2.2 g (20.1 mmol) of2-amino-5-methyl-pyridine and 11.4 g (50.0 mmol) of2-hydroxy-cyclohexanone dimer in 120 ml of 1,2-dichlorobenzene for 6 h.11.4 g (50.0 mmol) of 2-hydroxy-cyclohexanone dimer are then added againand the mixture is boiled under reflux for a further 3 h. On cooling, aprecipitate is deposited at 20° C. 150 ml of acetone are added, themixture is cooled to 0° to 5° C. with stirring, and the precipitate isfiltered off with suction and washed with cold ether. The productobtained is dried over phosphorus pentoxide in a high vacuum; yield 18g.

R_(f) 0.29 (dichloromethane:ethanol=20:1)

The compounds of the following Table XIV are obtained in analogy to theprocedure of Example No. XIX:

                  TABLE XIV                                                       ______________________________________                                                                             Starting                                 Ex. No.                                                                             Heterocycle          R.sub.f (solvent)                                                                       material                                 ______________________________________                                        CXV                                                                                  ##STR123##          0.16 (C)                                           CXVI                                                                                 ##STR124##          0.37 (C)  Ex. No. CXIII                            CXVII                                                                                ##STR125##          0.17 (D)  Ex. No. CXIV                             ______________________________________                                    

EXAMPLE NO. CXVIII 1-Chloro-5,7-dimethyl-β-carboline ##STR126##

10.2 g (49 mmol) of the compound from Example No. CXV are reacted at125° C. for 24 h with 222 ml (2.4 mol) of phosphorus oxychloride and 155μl of N,N-dimethyl-aniline. The mixture is poured into 1 l of ice waterafter cooling, then neutralized with aqueous sodium carbonate solutionand extracted several times with ethyl acetate. The organic phase isdried with magnesium sulphate, evaporated and freed from the residualsolvent in a high vacuum The crude product is purified by chromatographyon silica gel 60 (Merck/dichioromethane);

yield: 4.3 g.

R_(f) =0.39 (dichloromethane:ethanol=20:1)

EXAMPLE NO. CXIX 5,7-Dimethyl-β-carboline ##STR127##

3.8 g (16.5 mmol) of the compound from Example CXVIII are reacted with1.3 g of sodium hydrogen carbonate on 700 mg of palladium (10%)/carbonat a hydrogen pressure of about 3 bar and 20° C. for 10 d in 40 ml ofTHF, 300 mg of palladium (10%)/carbon and 5 ml of methanol being addedon every second day. The catalyst is then filtered off with suctionthrough kieselguhr, washed with THF, boiled in methanol anddichloromethane and again filtered off with suction. The combinedorganic solutions are evaporated, and the residue is precipitated bystirring with ether and filtered off with suction. After vacuum drying,3 g of product are obtained.

R_(f) 0.13 (dichloromethane:ethanol=20:1)

EXAMPLE NO. CXX 5,6-Dimethyl-1-(pyrid-2-yl)-1H-benzotriazole ##STR128##

14.85 g (103 mmol) of 5,6-dimethyl-1H-benzolriazole are dissolved in 150ml of anhydrous DMSO, reacted with 5 g (104 mmol) of 50% strength sodiumhydride (+40% paraffin oil) at 20° C. until evolution of hydrogen iscomplete, treated with 10 g (103 mmol) of 2-fluoro-pyridine and themixture is boiled under reflux for 18 h. After cooling to 20° C., themixture is made up to a volume of about 1 l with water, and theresulting precipitate is filtered off with suction and washed withwater. The substance, which is dried over phosphorus pentoxide in a highvacuum, is purified by chromatography on silica gel 60(Merck/dichloromethane to dichloromethane:ethanol=100:1);

yield: 10.6 g.

R_(f) =0.38 (dichloromethane:ethanol=50:1)

EXAMPLE NO. CXXI 6,7-Dimethyl-α-carboline ##STR129##

8.9 g (39.7 mmol) of the compound from Example No. CXX are slowly heatedto 165° C. in 140 g of polyphosphoric acid under argon, the mixturebeing poured into 1.5 l of water and adjusted to pH=6-7 with 1M aqueoussodium hydroxide solution before disappearance of the starting material(TLC checking/dichloromethane:ethanol=20:1). The precipitate obtained isfiltered off with suction, washed with water, rapidly filtered off withsuction, then washed with petroleum ether and filtered off with suctionagain. After vacuum drying 1.8 g of product are obtained.

R_(f) 0.32 (dichlommethane:ethanol=20:1)

The compounds in Table XV are prepared in analogy to the procedure ofExample No. XXI:

                  TABLE XV                                                        ______________________________________                                        Ex. No.                       R.sub.f (solvent)                               ______________________________________                                        CXXII                                                                                  ##STR130##           0.56 (H)                                        CXXIII                                                                                 ##STR131##                                                           CXXIV                                                                                  ##STR132##                                                           ______________________________________                                    

The compounds in Table XVI are prepared in analogy to the procedure ofExample No. XXVIII:

                  TABLE XVI                                                       ______________________________________                                                                            Starting                                                             R.sub.f  material                                  Ex. No.                    (solvent)                                                                              (Ex. No.)                                 ______________________________________                                        CXXV                                                                                  ##STR133##         0.40 (H) CXXII                                     CXXVI                                                                                 ##STR134##                  CXXIII                                    CXXVII                                                                                ##STR135##                  CXXIV                                     ______________________________________                                    

                                      TABLE XVII                                  __________________________________________________________________________     ##STR136##                                                                                           Position                      Starting material       Ex. No.                                                                             Z                 (o, m or p)                                                                         1 D      R.sup.10                                                                         R.sub.f (solvent)                                                                   MS    Ex.                     __________________________________________________________________________                                                          No.                     CXXVIII                                                                              ##STR137##       p     --                                                                              H      Me 0.59 (G)                                                                            DCI: 359                                                                            XIX0%)                  CXXIX                                                                                ##STR138##       p     rac                                                                             cPent  Me 0.51 (D)    XXXIII                  CXXX                                                                                 ##STR139##       p     rac                                                                             cPent  Me 0.22 (C)    XXXIII (Harman is                                                             commercially                                                                  available from                                                                Aldrich).               CXXXI                                                                                ##STR140##       m     rac                                                                             cPent  Me 0.55 (D)    XIX and CXXV            CXXXII                                                                               ##STR141##       p     rac                                                                             cPent  Me 0.21 (D)    CXVI and XXXIII         CXXXIII                                                                              ##STR142##       p     rac                                                                             cPent  tBu            XXVIII and CXXI         CXXXIV                                                                               ##STR143##       p     rac                                                                             cPent  tBu            XXVIII and CXVII        CXXXV                                                                                ##STR144##       p     rac                                                                             cPent  tBu            XXVIII and CXIX         CXXXVI                                                                               ##STR145##       p     rac                                                                             cPent  Me 0. 13 (L)   XXXIII                  CXXXVII                                                                              ##STR146##       p     rac                                                                             Me     tBu                                                                              0.43 (L)    XIX                     CXXXVIII                                                                             ##STR147##       p     rac                                                                             Et     tBu                                                                              0.51 (L)    XIX                     CXXXIX                                                                               ##STR148##       p     rac                                                                             nPent  Et             XIX and CXXVII          CXL                                                                                  ##STR149##       p     rac                                                                              ##STR150##                                                                          Et             XIX and                 __________________________________________________________________________                                                          CXXVI               

                                      TABLE XVIII                                 __________________________________________________________________________     ##STR151##                                                                                                                           Preparation                                  Position                 Starting                                                                              analogous to          Ex. No.                                                                           Z                  (o, m or p)                                                                         1  D      R.sub.f (solvent)                                                                   MS Ex. No. Ex.                   __________________________________________________________________________                                                            No.                   CXLI                                                                               ##STR152##        p     -- H      0.56 (O) CXXVIII   LXXXI               CXLII                                                                              ##STR153##        p     rac                                                                              cPent  0.14 (G) CXXIX     LXXXI               CXLIII                                                                             ##STR154##        p     rac                                                                              cPent  0.50 (U) CXXX      LXXXI               CXLIV                                                                              ##STR155##        m     rac                                                                              cPent  0.14 (D) CXXXI     LXXXI               CVL                                                                                ##STR156##        p     rac                                                                              cPent  0.10 (D) CXXXII    LXXXI               CVLI                                                                               ##STR157##        p     rac                                                                              cPent  0.34 (C) CXXXIII   LXI                 CVLII                                                                              ##STR158##        p     rac                                                                              cPent           CXXXIV    LXI                 CVLIII                                                                             ##STR159##        p     rac                                                                              cPent  0.15 (C) CXXXV     LXI                 CIL                                                                                ##STR160##        p     rac                                                                              cPent           CXXXVI    LXXXI               CL                                                                                 ##STR161##        p     rac                                                                              Et              CXXXVIII  LXI                 CLI                                                                                ##STR162##        p     rac                                                                              Me              CXXXVII   LXI                 CLII                                                                               ##STR163##        p     rac                                                                              nPent           CXXXIX    LXXXI               CLIII                                                                              ##STR164##        p     rac                                                                               ##STR165##     CXL       LXXXI               __________________________________________________________________________

PREPERATION EXAMPLES Examples 1, 2 and 3 2-(S)- and 2-(R)-2-4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- (R)-phenylglycinolamide! ##STR166##

3.00 g (7.2 mmol of the compound from Example LXII are dissolved in 70ml of dichloromethane with 0.99 g (7.2 mmol) of (R)-phenylglycinol(Aldrich), and the solution is treated successively at 0° C. with 1.07 g(7.9 mmol) of 1-hydroxy-1H-benzotriazole hydrate (Aldrich), 1.58 g (8.3mmol) of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride(Aldrich) and 2 ml of triethylamine and then stirred at room temperaturefor 20 hours. The organic solution is extracted with aqueous ammoniumchloride solution, with aqueous sodium hydrogen carbonate solution andwith a buffer of pH=4 (ready-to-use buffer solution, E. Merck,Darmstadt), dried with solid anhydrous sodium sulphate and evaporated.

Yield of the diastereomer mixture: 3.50 g (Example 1).

The product mixture is separated by chromatography (silica gel,dichloromethane : ethanol=50:1):

Example No. 2:

Diastereomer A 2(S)<diastereomer!: 1.23 g

R_(f) 0.18 (dichloromethane:ethanol=50:1)

c¹ H-NMR (d-DMSO, 250 MHz, TMS): δ=0.87 (M, 1H), 1.19-1.63 (M, 6H), 1.72(M, 1H), 2.45 (M, 1H), 2.58 (S, 3H), 2.79 (S, 3H, 3.26 (D, 1H),3.44-3.53 (M, 2H), 4.21-4.31 (M, 2H, 5.63(S, 2H), 6.97-7.11 (M, 8H),7.20-7.28(M, 3H) 7.41 (M, 1H) 7.54 (D, 1H), 8.12 (D, 1H), 8.24 (D,1H)ppm

Example No. 3:

Diastereomer B 2CR)-diastereomer!: 1.12 g

R_(f) =0.16 (dichloromethane:ethanol=50:1)

¹ H-NMR (d-DMSO, 250 MHz, TMS): δ=0.84 (M, 1H, 1.07-1.59 (M, 7H, 2.34(M, 1H), 2.61 (S, 3H), 2.80 (S, 3H), 3.25 (D, 1H), 3.43 (M, 2H),4.63-4.72 (M, 2H, 5.66 (S, 2H), 6.98 (S, 1H), 7.13 (M, 2H), 7.20-7.30(M, 8H), 7.43 (M, 1H), 7.57 (D, 1H), 8.12 (D, 1H), 8.36 (D, 1H) ppm.

The absolute configurations of the enantiomerically pure carboxylicacids 2-(S)- and 2-(R)-2-{4-(quinolin-2-yl)methoxy!phenyl}-2-cyclopentyl-acetic acid cf. EP 509 359!are known, so the absolute configurations of the amides Ex. No. C1 andEx. No. C2 prepared therefrom analogously to the procedure of Examples 1and 2 can be derived. The ¹ H-NMR spectra of the two diastereomericproducts (200 MHz, d₆ -DMSO, TMS for Example No. C1 and 250 MHz, d₆-DMSO, TMS for Example No. C2/FIG. 1) have significant differences inthe aromatic region: the H signals of the phenyl radical of Ex. No. C1are at about 7.1 ppm (3H) and 7.3 ppm (2H) and the H signals of Ex. No.C2 are at about 7.3 ppm (5H). This finding is applicable to thecompounds of Examples 2 and 3 (FIG 2) and also to many other derivativesof this type.

The examples mentioned in Tables 1, 2 and 3 are prepared in analogy tothe procedure of Examples 1, 2 and 3:

                                      TABLE 1                                     __________________________________________________________________________     ##STR167##                                                                                                       Starting material*                        Ex. No.                                                                           Z                   D  1 R.sub.f (solvent)                                                                    (Ex. No.)                                 __________________________________________________________________________     4                                                                                 ##STR168##         cPent                                                                            rac                                                                             0.41/0.46 (E)                                                                        LXI                                        5                                                                                 ##STR169##         cPent                                                                            S 0.46 (E)                                                                             LXI                                        6                                                                                 ##STR170##         cPent                                                                            R 0.41 (E)                                                                             LXI                                        7                                                                                 ##STR171##         cHept                                                                            rac                                                                             0.26/0.29 (D)                                                                        LXIII                                      8                                                                                 ##STR172##         cHept                                                                            S 0.29 (D)                                                                             LXIII                                      9                                                                                 ##STR173##         cHept                                                                            R 0.26 (D)                                                                             LXIII                                     10                                                                                 ##STR174##         cHept                                                                            rac                                                                             0.20/0.24 (E)                                                                        LXIV                                      11                                                                                 ##STR175##         cHept                                                                            S 0.24 (E)                                                                             LXIV                                      12                                                                                 ##STR176##         cHept                                                                            R 0.20 (E)                                                                             LXIV                                      13                                                                                 ##STR177##         cHept                                                                            rac                                                                             0.35 (C)                                                                             LXV                                       14                                                                                 ##STR178##         cHept                                                                            S 0.35 (C)                                                                             LXV                                       15                                                                                 ##STR179##         cHept                                                                            R 0.35 (C)                                                                             LXV                                       16                                                                                 ##STR180##         cPent                                                                            rac                                                                             0.33/0.37 (C)                                                                        LXVI                                      17                                                                                 ##STR181##         cHept                                                                            rac                                                                             0.25/0.38 (C)                                                                        LXVII                                     18                                                                                 ##STR182##         cHept                                                                            S 0.38 (C)                                                                             LXVII                                     19                                                                                 ##STR183##         cHept                                                                            R 0.25 (C)                                                                             LXVII                                     20                                                                                 ##STR184##         cPent                                                                            rac                                                                             0.29 (A)                                                                             LXVIII                                    21                                                                                 ##STR185##         cHept                                                                            rac                                                                             0.23/0.28 (D)                                                                        LXIX                                      22                                                                                 ##STR186##         cHept                                                                            S 0.28 (D)                                                                             LXIX                                      23                                                                                 ##STR187##         cHept                                                                            R 0.23 (D)                                                                             LXIX                                      24                                                                                 ##STR188##         cHept                                                                            rac                                                                             0.10/0.18 (E)                                                                        LXX                                       25                                                                                 ##STR189##         cHept                                                                            S 0.18 (E)                                                                             LXX                                       26                                                                                 ##STR190##         cHept                                                                            R 0.10 (E)                                                                             LXX                                       27                                                                                 ##STR191##         cHept                                                                            rac                                                                             0.17/0.23 (B)                                                                        LXXXI                                     28                                                                                 ##STR192##         cHept                                                                            rac                                                                             0.12/0.15 (B)                                                                        LXXXIV                                    29                                                                                 ##STR193##         cPent                                                                            rac                                                                             0.28 (E)                                                                             LXXI                                      30                                                                                 ##STR194##         cPent                                                                            rac                                                                             0.29 (C)                                                                             LXXII                                     31                                                                                 ##STR195##         cPent                                                                            rac                                                                             0.24 (C)                                                                             LXXIII                                    32                                                                                 ##STR196##         cPent                                                                            rac                                                                             0.39/0.48 (C)                                                                        LXXIV                                     33                                                                                 ##STR197##         cPent                                                                            S 0.48 (C)                                                                             LXXIV                                     34                                                                                 ##STR198##         cPent                                                                            R 0.39 (C)                                                                             LXXIV                                     35                                                                                 ##STR199##         cHept                                                                            rac                                                                             0.23/0.29 (D)                                                                        LXXV                                      36                                                                                 ##STR200##         cPent                                                                            rac                                                                             0.26 (A)                                                                             LXXVI                                     37                                                                                 ##STR201##         cHex                                                                             rac                                                                             0.28/0.30 (D)                                                                        LXXVII                                    38                                                                                 ##STR202##         cHex                                                                             rac                                                                             0.21/0.23 (D)                                                                        LXXVIII                                   __________________________________________________________________________     *(R)-Phenylglycinol is commercially available from Aldrich.              

                                      TABLE 2                                     __________________________________________________________________________     ##STR203##                                                                                                 Starting material*                              Ex. No.               1 R.sub.f (solvent)                                                                   (Ex. No.)                                       __________________________________________________________________________    39                                                                                 ##STR204##       rac                                                                             0.42 (C)                                                                            LXI                                             40                                                                                 ##STR205##       R 0.42 (C)                                                                            LXI                                             41                                                                                 ##STR206##       S 0.42 (C)                                                                            LXI                                             __________________________________________________________________________     *(S)-Phenylglycinol is commercially available from Aldrich.              

                                      TABLE 3                                     __________________________________________________________________________     ##STR207##                                                                                                                  Starting material              Ex. No.                                                                           Z                  D  X          1   R.sub.f (solvent)                                                                   (Ex. No.)                      __________________________________________________________________________    42                                                                                 ##STR208##        cHept                                                                            H          rac 0.39 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXIII Amine from Aldrich       43                                                                                 ##STR209##        cHept                                                                            H          rac 0.78 (E)                                                                            Carboxylic acid: Ex. No.                                                      LXIV Amine from Aldrich        44                                                                                 ##STR210##        cPent                                                                            H          rac 0.34 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXII Amine from Aldrich        45                                                                                 ##STR211##        cPent                                                                            H          (-)-ent*                                                                          0.34 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXII Amine from Aldrich        46                                                                                 ##STR212##        cPent                                                                            H          (+)-ent*                                                                          0.34 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXII Amine from Aldrich        47                                                                                 ##STR213##        cHept                                                                            H          rac 0.25 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         48                                                                                 ##STR214##        cHept                                                                            H          rac 0.42 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXVII Amine from Aldrich       49                                                                                 ##STR215##        cHept                                                                            H          rac 0.45 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXIX Amine from Aldrich        50                                                                                 ##STR216##        cHept                                                                            H          rac 0.71 (E)                                                                            Carboxylic acid: Ex. No.                                                      LXX Amine from Aldrich         51                                                                                 ##STR217##        cHept                                                                            H          rac 0.59 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXXXI Amine from Aldrich       52                                                                                 ##STR218##        cHept                                                                            H          rac 0.40 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXXXIV Amine from Aldrich      53                                                                                 ##STR219##        cHept                                                                            3-OH       rac 0.45 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ref.: US 43 88                                                     250                            54                                                                                 ##STR220##        cHept                                                                            4-OH       rac 0.39 (A)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ref.: C.                                                           Hartmann and J. P.                                                            Klinman, Biochemistry, 30,                                                    605 (1991)                     55                                                                                 ##STR221##        cHept                                                                            2-OCH.sub.3                                                                              rac 0.15 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         56                                                                                 ##STR222##        cHept                                                                            3-OCH.sub.3                                                                              rac 0.37 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Lancaster       57                                                                                 ##STR223##        cHept                                                                            4-OCH.sub.3                                                                              rac 0.25 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         58                                                                                 ##STR224##        cHept                                                                            2-OCH.sub.2CHCH.sub.2                                                                    rac 0.51 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ex. No. II          59                                                                                 ##STR225##        cHept                                                                            3-CO.sub.2 CH.sub.3                                                                      rac 0.73 (C)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ref.: F. M.                                                        Markwardt et al.,                                                             Pharmazie 22, 465 (1967).      60                                                                                 ##STR226##        cHept                                                                            4-CO.sub.2 CH.sub.3                                                                      rac 0.33 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ref.: M. G.                                                        Nair and C. M. Baugh, J.                                                      Org. Chem. 38, 2185                                                           (1973).                        61                                                                                 ##STR227##        cHept                                                                            3-CH.sub.3 rac 0.19 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         62                                                                                 ##STR228##        cHept                                                                            2-NO.sub.2 rac 0.39 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine: Ref.: EP 373                                                       891                            63                                                                                 ##STR229##        cHept                                                                            3-NO.sub.2 rac 0.28 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         64                                                                                 ##STR230##        cHept                                                                            4-NO.sub.2 rac 0.21 (B)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         65                                                                                 ##STR231##        cHept                                                                            2-Cl       rac 0.75 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         66                                                                                 ##STR232##        cHept                                                                            3-Cl       rac 0.71 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Lancaster       67                                                                                 ##STR233##        cHept                                                                            4-Cl       rac 0.61 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXV Amine from Aldrich         68                                                                                 ##STR234##        cPent                                                                            H          rac 0.28 (D)                                                                            Carboxylic acid: Ex. No.                                                      LXI Amine from                 __________________________________________________________________________                                                   Aldrich                         *Resolution of enantiomers is carried out by means of HPLC (Chiralpak AD,     length 250 mm, diameter 4.6 mm, particle size 10μ, eluent: 95% nheptan     + 5% ethanol (the latter containing 1% water and 0.2% trifluoroacetic         acid)).                                                                  

EXAMPLE 69 2-(R,S)-2-4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl!-2-cycloheptyl-aceticacid N-(2-hydroxybenzyl)amide ##STR235##

0.60 g of the compound from Example 58 are boiled under reflux for 22hours with 33 mg of palladium (10% on animal carbon) and 33 mg ofpara-toluenesulphonic acid monohydrate in 3 ml of methanol and 0.6 ml ofwater under argon as a protective gas. If reaction is incomplete (TLCchecking dichloromethane:ethanol=50:1), 33 mg of palladium (10% onanimal carbon) and 33 mg of para-toluenesulphonic acid monohydrate areadded once more and the mixture is boiled under reflux for a further 24hours. The catalyst is filtered off hot with suction and washed withplenty of hot methanol, and the filtrate is evaporated. After drying ina high vacuum over phosphorus pentoxide, 0.52 g of product are obtained.

R_(f) =0.33 (dichloromethane:ethanol=50:1)

EXAMPLE 70 2-(R,S)-2-4-(3-Hydroxymethyl-β-carbolin-9-yl)-methyl-phenyl!-2-cyclo-pentyl-aceticacid N-(R)-phenylglycinolamide ##STR236##

500 mg (0.868 mmol) of the compound from Example 31 are treated dropwisewith 1.737 ml (1.737 mmol) of a 1M lithium aluminium hydride solution intetrahydrofuran under argon at 0° C. in 5 ml of anhydroustetrahydrofuran and stirred at about 20° C. for 4 h. The reactionmixture is treated cautiously with 5 ml of water and adjusted to a pH ofabout 2 using 2M aqueous hydrochloric acid. The aqueous phase isextracted several times with diethyl ether and dichloromethane, driedwith sodium sulphate and evaporated. The crude product is purified bychromatography on silica gel 60 (Merck, dichloromethane todichloromethane:methanol=50:1).

Yield: 0.12 g

R_(f) =0.26 (dichloromethane:ethanol=20:1)

The compounds of Table 4 are prepared in analogy to the procedure ofExample 70:

                  TABLE 4                                                         ______________________________________                                         ##STR237##                                                                   Ex. No. Y        1       R.sub.f (solvent)                                                                     Starting material                            ______________________________________                                        71      4-CH.sub.2 OH                                                                          rac     0.47 (C)                                                                              Ex. No. 60                                   72      3-CH.sub.2 OH                                                                          rac     0.26 (C)                                                                              Ex. No. 59                                   ______________________________________                                    

EXAMPLE 73 2-(R,S)-2-4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl!-2-cycloheptyl-aceticacid N-(4-carboxybenzyl)amide ##STR238##

0.325 g (0.55 mmol) of the compound from Example 60 is reacted at 60° C.with 0.5 ml of aqueous 2M sodium hydroxide solution in 3 ml of methanolfor 18 h. If the reaction is still not complete according to thin-layeranalysis (solvent F), a further 0.5 ml of aqueous 2M sodium hydroxidesolution in 1 ml of methanol is added and the mixture is then boiledunder reflux for 24 h. The reaction mixture is cooled and adjusted to apH of about 4 using 1M hydrochloric acid, and the precipitate which isdeposited is filtered off with suction, washed with water and petroleumether:diethyl ether=5:1 and freed from the residual solvents in a highvacuum over phosphorus pentoxide.

Yield: 0.154 g

R_(f) =0.50 (dichloromethane:methanol:acetic acid=90:10:2)

EXAMPLE 74 2-(R,S)-2-4-(2,4-Dimethyl-5,6,7,8-tetrahydro-α-carbolin-9-yl)-methyl-phenyl!-2-cycloheptyl-aceticacid N-(3-carboxybenzyl)amide ##STR239##

The title compound can be prepared from the compound of Example 59analogously to the procedure of Example 73.

R_(f) =0.27 (dichloromethane:ethanol=20:1)

The compounds shown in Tables 5, 6, 7, 8, 9 and 10 are prepared inanalogy to the procedure of Example 1:

                  TABLE 5                                                         ______________________________________                                         ##STR240##                                                                   Ex. No.                                                                             Y      1     M.p.   Starting material                                   ______________________________________                                        75    3-OH   rac   177-178                                                                              Carboxylic acid:                                                              Ex. No. LXII                                                                  Amine: US 43 88 250                                 76    4-OH   rac   183-184                                                                              Carboxylic acid:                                                              Ex. No. LXII                                                                  Amine: Ref.: C. Hartmann and                                                  J. P. Klinman, Biochemistry 30, 4605                                          (1991)                                              ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                         ##STR241##                                                                   Ex. No.                                                                             R.sup.5    R.sub.f (solvent)                                                                       Starting material                                  ______________________________________                                        77                                                                                   ##STR242##                                                                              0.20 (C)  Carboxylic acid: Ex. No. LXV Amine from                                       Aldrich                                            78                                                                                   ##STR243##                                                                              0.12 (C)  Carboxylic acid: Ex. No. LXV Amine from                                       Aldrich                                            79                                                                                   ##STR244##                                                                              0.19 (C)  Carboxylic acid: Ex. No. LXV Amine from                                       Aldrich                                            80                                                                                   ##STR245##                                                                              0.24 (D)  Carboxylic acid: Ex. No. LXV Amine from            ______________________________________                                                                   Aldrich                                             *racemic                                                                 

                  TABLE 7                                                         ______________________________________                                         ##STR246##                                                                   Ex. No.                                                                             1     R.sup.20     R.sub.f (solvent)                                                                     Starting material                            ______________________________________                                        81    rac                                                                                  ##STR247##  0.10 (P)                                                                              Acid: Ex. No. LXXIX Amine from Aldrich       82    rac                                                                                  ##STR248##  0.28 (P)                                                                              Acid: Ex. No. LXXIX Amine from               ______________________________________                                                                         Aldrich                                  

                                      TABLE 8                                     __________________________________________________________________________     ##STR249##                                                                                             Starting material                                                             a) Reference                                                      M.p. (°C.)                                                                         b) Distributor                                      Ex. No.                                                                           1 X   Y   R.sub.f (solvent)                                                                   MS (FAB)                                                                            c) Synthesis from Ex. No.                           __________________________________________________________________________    83  rac                                                                             3-OCH.sub.3                                                                       4-OCH.sub.3                                                                       179   562 (100%)                                                                          Carboxylic acid:                                                  0.50 (A)                                                                            154 (80%)                                                                           c) Ex. No. LXI                                                                Amine from Aldrich.                                 84  rac                                                                             3-CH.sub.3                                                                        5-CH.sub.3                                                                        212   530 (100%)                                                                          Carboxylic acid:                                                  0.60 (B)    c) Ex. No. LXI                                                                Amine from Emka-Chemie.                             85  rac                                                                             3-Cl                                                                              5-Cl                                                                              212   570 (100%)                                                                          Carboxylic acid:                                                  0.18 (M)                                                                            196 (50%)                                                                           c) Ex. No. LXI                                                                Amine from Maybridge.                               86  rac                                                                             3-OH                                                                              4-OH                                                                              137   534 (100%)                                                                          Carboxylic acid:                                                  0.39 (A)                                                                            307 (60%)                                                                           c) Ex. No. LXI                                                                Amine from Aldrich.                                 87  rac                                                                             3-OCH.sub.3                                                                       4-OH                                                                              135   548 (80%)                                                                           Carboxylic acid:                                                  0.65 (A)                                                                            154 (100%)                                                                          c) Ex. No. LXI                                                                Amine from Aldrich.                                 __________________________________________________________________________

                  TABLE 9                                                         ______________________________________                                         ##STR250##                                                                                                    Starting material*                                                            a) Reference                                 Ex.               M.p. (°C.)                                                                      MS    b) Distributor                               No.  1     D      R.sub.f (solvent)                                                                      (FAB) c) Synthesis from Ex. No.                    ______________________________________                                        88   rac   iPr    210      506   Carboxylic acid:                                               0.37/0.31 (A)                                                                          (100%)                                                                              Ex. No. LXXXII                                                          154                                                                           (60%)                                              89   rac   iBu    --       520   Carboxylic acid:                                               0.30 (A) (100%)                                                                              Ex. No. LXXX                                                            154                                                                           (50%)                                              ______________________________________                                         *(R)-Phenylglycinol is commercially available from Aldrich.              

                                      TABLE 10                                    __________________________________________________________________________     ##STR251##                                                                                                   M.p. (°C.)                                                                   Starting material                       Ex. No.                                                                           Z                  R.sup.21 R.sub.f (solvent)                                                                   from Ex. No.                            __________________________________________________________________________    90                                                                                 ##STR252##                                                                                       ##STR253##                                                                            188-189                                                                             LXXXIX                                  91                                                                                 ##STR254##                                                                                       ##STR255##                                                                            0.024 (P)                                                                           LXXXIX                                  92                                                                                 ##STR256##                                                                                       ##STR257##                                                                            207-208                                                                             XC                                      93                                                                                 ##STR258##                                                                                       ##STR259##                                                                            211-212                                                                             XC                                      __________________________________________________________________________     *racemic                                                                 

The compounds of Table 11 are prepared analogously to the procedure ofExample Nos. 1, 2 and 3:

                                      TABLE11                                     __________________________________________________________________________     ##STR260##                                                                                               M.p. (°C.)                                                                         Starting material                     Ex. No.                                                                           Z                 D  1  R.sub.f (solvent)                                                                   MS (FAB)                                                                            from Ex. No.                          __________________________________________________________________________     94                                                                                ##STR261##       cHept                                                                            S  0.23 (B)    27                                     95                                                                                ##STR262##       cHept                                                                            R  0.17 (B)    27                                     96                                                                                ##STR263##       cPent                                                                            S  0.29 (A)    20                                     97                                                                                ##STR264##       cPent                                                                            R  0.29 (A)    20                                     98                                                                                ##STR265##       cHex                                                                             S  0.23 (D)    38                                     99                                                                                ##STR266##       cHex                                                                             R  0.21 (D)    38                                    100                                                                                ##STR267##       iPr                                                                              S  208° C.                                                                      506 (100%) 154 (40%)                                                                88                                    101                                                                                ##STR268##       iPr                                                                              R  204° C.                                                                      506 (100%) 154 (40%)                                                                88                                    102                                                                                ##STR269##       iBu                                                                              S  182° C.                                                                            89                                    103                                                                                ##STR270##       iBu                                                                              R  206° C.                                                                            89                                    104                                                                                ##STR271##       cPent                                                                            rac                                                                              0.34 (C)    CV                                    105                                                                                ##STR272##       cPent                                                                            rac                                                                              0.44 (E) 0.56                                                                             CVI                                   106                                                                                ##STR273##       cPent                                                                            S  0.56 (E)                                                                            586 (100%) 154 (94%)                                                                CVI                                   107                                                                                ##STR274##       cPent                                                                            R  0.44 (E)    CVI                                   108                                                                                ##STR275##       cPent                                                                            rac                                                                              0.26 (E) 0.31                                                                             CVII                                  109                                                                                ##STR276##       cPent                                                                            S  0.55 (C)    CVII                                  110                                                                                ##STR277##       cPent                                                                            R  0.57 (C)    CVII                                  111                                                                                ##STR278##       cPent                                                                            rac                                                                              0.45 (C)    CVIII                                 112                                                                                ##STR279##       cPent                                                                            rac                                                                              0.4 C       CIX                                   113                                                                                ##STR280##       cPent                                                                            rac                                                                              0.37 C      CX                                    114                                                                                ##STR281##       cPent                                                                            S  0.37 (C)    CX                                    115                                                                                ##STR282##       cPent                                                                            R  0.37 (C)    CX                                    116                                                                                ##STR283##       cPent                                                                            diaA                                                                             194° C.                                                                            81                                    117                                                                                ##STR284##       cPent                                                                            diaB                                                                             137° C.                                                                            81                                    __________________________________________________________________________

The compounds of Table 12 are prepared analogously to the procedure ofExample Nos. 1, 2 and 3:

                                      TABLE 12                                    __________________________________________________________________________     ##STR285##                                                                                         M.p. (°C.)                                                                         Starting material                           Ex. No.                                                                           1 R.sup.22        R.sub.f (solvent)                                                                   MS (FAB)                                                                            from Ex. No.                                __________________________________________________________________________    118 rac                                                                              ##STR286##     0.82 (C)                                                                            574 (100%)                                                                          LXI                                         119 rac                                                                              ##STR287##     0.57 (C) 0.62                                                                       576 (100%)                                                                          LXI                                         120 rac                                                                              ##STR288##     0.43 (C) 0.48                                                                             LXI                                         121 rac                                                                              ##STR289##     0.52 (C)    LXI                                         122 rac                                                                              ##STR290##     0.47 (C)    LXI                                         123 rac                                                                              ##STR291##     0.17 (D) 0.32                                                                             LXI                                         124 rac                                                                              ##STR292##     0.43 (C)    LXI                                         125 rac                                                                              ##STR293##     0.57 (C)    LXI                                         126 rac                                                                              ##STR294##     0.41 (C)    LXI                                         127 rac                                                                              ##STR295##     0.14 (C)    137                                         128 S                                                                                ##STR296##     187° C.                                                                      548 (100%) 154 (80%) 137 (85%)                                                      LXI                                         __________________________________________________________________________

The compounds of Table 13 are prepared analogously to the procedure ofExample No. 73:

                  TABLE 13                                                        ______________________________________                                         ##STR297##                                                                                                           Starting                              Example                         M.p.  °C.!                                                                     material from                         No.    1/2     X      Y    Z    R.sub.f (solvent)                                                                     Ex. No.                               ______________________________________                                        129    rac/rac H      H    H    0.15 (S)                                                                              118                                   130    rac/rac H      OH   H    0.18 (T)                                                                              119                                                                   0.24                                          131    rac/rac H      H    OH   0.68 (S)                                                                              120                                                                   0.76                                          132    rac/rac OH     H    H    0.16 (T)                                                                              121                                                                   0.24                                          ______________________________________                                    

The compounds of Table 14 are prepared analogously to the procedure ofExample No. 70:

                  TABLE 14                                                        ______________________________________                                         ##STR298##                                                                                                           Starting                              Example                         M.p.  °C.!                                                                     material from                         No.    1/2     X      Y    Z    R.sub.f (solvent)                                                                     Ex. No.                               ______________________________________                                        133    rac/rac H      OH   H    0.30 (A)                                                                              119                                   134    rac/rac H      H    OH   0.25 (A)                                                                              120                                   135    rac/rac OH     H    H    0.33 (A)                                                                              121                                   136    rac/rac H      OH   OH   0.23 (A)                                                                              122                                   137    rac/rac H      H    NH.sub.2                                                                           0.31 (C)                                                                              125                                   ______________________________________                                    

EXAMPLE NO. 138 2-(R,S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!2-cyclopentylacetic acidN- 1-(R,S)-1-(4-acetamido-phenyl)-2-hydroxy-ethyl!amide ##STR299## PartA)

0.60 g (1.10 mmol) of the compound from Example No. 137 is treated with192 μl (3.29 mmol) of triethylamine in 10 ml of dichloromethane and thenreacted at 0° C. with 70 μl (0.99 mmol) of acetyl chloride. After astirring time of 3 hours, in which the reaction temperature rises to 20°C., the mixture is shaken successively with 1M hydrochloric acid, 0.1Maqueous sodium hydroxide solution and water, and the organic phase isdried with magnesium sulphate and evaporated.

Part B)

The crude product thus obtained shows a double acetylation (631, 57% M⁺+H/653, 6%, M⁺ +Na) in the mass spectrum (FAB). It is therefore reactedwith 2M sodium hydroxide solution at 20° C. for one hour in 6 ml ofmethanol. The pH is then adjusted to 2 using 1M hydrochloric acid andthe mixture obtained is extracted with ethyl acetate. The organic phaseis washed with water until neutral, dried with magnesium sulphate andevaporated in vacuo. Drying in a high vacuum yields 0.28 g of product.

R_(f) =0.17 (Dichloromethane:ethanol=20:1)

EXAMPLE NO. 139 2-(R,S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(R,S)-1-(4-acetamido-phenyl)-2-acetoxy-ethyl!amide ##STR300##

If the compound from Example No. 137 is reacted with 4 equivalents eachof triethylamine and acetyl chloride analogously to Part A of theprocedure from Example No. 138, the title compound is obtained.

R_(f) =0.56 (Dichloromethane:ethanol=20:1)

The compounds of Table 15 are prepared analogously to the procedure ofExample No. 138:

                  TABLE 15                                                        ______________________________________                                         ##STR301##                                                                   Example                  M.p.  °C.!                                                                      Starting material                           No.     1/2      R.sup.23                                                                              R.sub.f (solvent)                                                                      from Ex. No.                                ______________________________________                                        140     rac/rac  nBu     0.49 (A) 137                                         141     rac/rac  Et      0.18 (U) 137                                         ______________________________________                                    

EXAMPLE NO. 142 2-(S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(R)-1-phenyl-2-acetoxy-ethyl!amide ##STR302##

4.5 g (8.46 mmol) of the compound No. 2 are suspended in 300 ml ofdichloromethane, treated with 2.05 ml (25.4 mmol) of pyridine and 1.82ml (25.4 mmol) of acetyl chloride in 30 ml of dichloromethane andreacted at 20° C. for 20 hours. The mixture is extracted with buffer(Merck) of pH=2 and water, dried with sodium sulphate and evaporated.After precipitating by stirring with methanol and subsequently drying ina high vacuum over phosphorus pentoxide, 3.6 g of product are obtained.

R_(f) =0.62 (Petroleum ether:ethyl acetate=1:1)

The compounds of Table 16 are prepared analogously to the procedure ofExample No. 142:

                                      TABLE 16                                    __________________________________________________________________________     ##STR303##                                                                                           M.p.  °C.!                                                                   Starting material                               Example No.                                                                         R.sup.24          R.sub.f (solvent)                                                                   from Ex. No.                                    __________________________________________________________________________    143   Et                0.25 (D)                                                                            2                                               144   CH.sub.2 OAc      0.29 (D)                                                                            2                                               145   CH.sub.2 OCH.sub.2 Ph                                                                           0.27 (D)                                                                            2                                               146   cis-(CH.sub.2).sub.7ZCHCH(CH.sub.2).sub.7 CH.sub.3                                              0.52 (D)                                                                            2                                               147   (CH.sub.2).sub.14CH.sub.3                                                                       0.69 (G)                                                                            2                                               148   Ph                0.65 (C)                                                                            2                                               149                                                                                  ##STR304##             2                                               150                                                                           tBu   0.38 (C)          2                                                     __________________________________________________________________________

EXAMPLE NO. 151 2-(S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-thioaceticacidN- 1-(R)-1-phenyl-2-acetoxy-ethyl!amide ##STR305##

1.5 g (2.6 mmol) of the compound from Example No. 142 are treated with1.27 g (3.13 mmol) of2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide(Lawesson's reagent) in 50 ml of dioxane and boiled under reflux for 5hours. The reaction mixture is evaporated to dryness in vacuo andpurified by chromatography on silica gel MATREX^(TR) silica Si (Amicon,Grace Company/20μ/MPLC column/dichloromethane:ethanol=100:1); yield: 665mg.

R_(f) =0.53 (Petroleum ether:ethyl acetate=2:1)

MS (FAB): m/e=612 (4% M+Na!⁺), 590 (100%, M+H!⁺), 529 (19%, M⁺ -AcOH).

EXAMPLE NO. 152 2-(S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(R)-1-phenyl-2- 2-hydroxy-acet)-oxy-!-ethyl!amide ##STR306##

1.45 g (2.13 mmol) of the compound from Example No. 145 are hydrogenatedwith hydrogen on palladium (5% on animal carbon) at 20° C. and normalpressure in 100 ml of THF. After 18 hours, the mixture is filtered offwith suction through kieselguhr, washed several times with methanol anddichloromethane, and the combined organic solutions are evaporated. Thesolid residue is stirred with pentane, filtered off with suction andfreed from the residual solvent in a high vacuum.

R_(f) =0.31 (Petroleum ether:ethyl acetate=1:1)

EXAMPLE NO. 153 2-(S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-thioaceticacidN- 1-(R)-1-phenyl-2-hydroxyethyl!-amide ##STR307##

The title compound is prepared at 20° C. from the compound of ExampleNo. 151 in DME as a solvent analogously to the synthesis procedure fromExample No. 73.

R_(f) =0.24 (Dichloromethane:ethanol=50:1)

EXAMPLE NO. 154 2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(thien-2-yl)-1-methoxycarbonyl-methyl!-amide ##STR308##

The title compound is prepared from the compound of Example No. LXII and(R,S)-(thien-2-yl)-glycine methyl ester analogously to the synthesisprocedure of Example Nos. 1, 2 and 3.

R_(f) =0.67 (Dichloromethane:ethanol=20:1)

EXAMPLE NO. 155 2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(thien-2-yl)-2-hydroxy-ethyl!-amide ##STR309##

The title compound is prepared from the compound of Example No. 154analogously to the synthesis procedure of Example No. 70.

R_(f) =0.21 (Dichloromethane:ethanol=50:1)

EXAMPLE NO. 156 2-(S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N- 1-(R)-1-phenyl-2-(2,4,6-trimethyl-benzoyl-oxy)-ethyl!-amide##STR310##

The compound is prepared from Example No. 2 is reacted to give the titlecompound analogously to the procedure of Example No. 142.

R_(f) =0.26 (Mobile phase D)

EXAMPLE NO. 157 1-(R,S)-1-Phenyl-2-triphenylmethyloxy-ethyl 2-(R, S )-2-4-(2,4-dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-acetate##STR311##

1.0 g (2.42 mmol) of the compound from Example LXI is reacted with 1 ml(7.27 mmol of triethylamine and 206 μl (2.67 mmol) of mesyl chloride in30 ml of DMF at -30° C. for 2 h, then treated dropwise with a solutionof 1.1 g (2.9 mmol) of the compound from Example No. CXI and 296 mg(2.42 mmol) of DMAP in 10 ml of DMF and stirred for about 20 h whilegradually warming to 20° C. For working up, the mixture is stirred intoether/water, the phases are separated, and the organic phase isextracted with aqueous 1M sodium hydroxide solution and washed withwater. The organic phase is dried with magnesium sulphate andevaporated--finally in a high vacuum; yield: 1.0 g.

R_(f) =0.44 (Petroleum ether:ethyl acetate=5:1)

EXAMPLES 158 and 159 1-(R,S)-1-Phenyl)-2-triphenylmethyloxy-ethyl2-(R,S)-2-4-(2,4-dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-acetate##STR312##

1.0 g (1.29 mmol) of the compound from Example No. 157 is stirred with 5ml of trifluoroacetic acid in 10 ml of THF and 5 ml of water at 20° C.for 48 h. The mixture is then stirred with 300 ml of ether and 200 ml ofaqueous sodium hydrogen carbonate solution, the phases are separatedafter evolution of carbon dioxide has subsided and the organic phase isextracted with buffer of pH=7 (Merck) and dried with magnesium sulphate.After evaporating the solvents, a crude product is obtained which ispurified by chromatography on silica gel (Merck/petroleum ether:ethylacetate=5:1) and separated into the diastereomers.

Racemic diastereomer A)

Yield: 300 mg

R_(f) =0.54 (Petroleum ether:ethyl acetate=2:1)

Racemic diastereomer B)

Yield: 320 mg

R_(f) =0.42 (Petroleum ether:ethyl acetate=2:1)

The compounds of Table 17 are prepared analogously to the procedure ofExample Nos. 1, 2 and 3:

                                      TABLE 17                                    __________________________________________________________________________     ##STR313##                                                                   Ex.                   Position                        Starting material       No. Z                 (o, m or p)                                                                          1   D      R.sub.f (solvent)                                                                    MS     Ex.                     __________________________________________________________________________                                                          No.                     160                                                                                ##STR314##       p      --  H      0.30 (C)                                                                             FAB: 464                                                                             CXLI%)                  161                                                                                ##STR315##       p      rac cPent  0.35 (C)                                                                             FAB: 504                                                                             CXLII                   162                                                                                ##STR316##       p      S   cPent  0.35 (C)      CXLII                   163                                                                                ##STR317##       p      R   cPent  0.35 (C)      CXLII                   164                                                                                ##STR318##       p      rac cPent  0.23/(C) 0.25                                                                        FAB: 518                                                                             CXLIII                  165                                                                                ##STR319##       p      R   cPent  0.29 (C)      CXLIII                  166                                                                                ##STR320##       p      S   cPent  0.25 (C)      CXLIII                  167                                                                                ##STR321##       m      rac cPent  0.40 (C)                                                                             FAB: 532                                                                             CXLIV)                  168                                                                                ##STR322##       p      rac cPent  0.26/0.22 (D)                                                                        FAB: 518                                                                             CVL0%)                  169                                                                                ##STR323##       p          cPent  0.26 (D)      CVL                     170                                                                                ##STR324##       p          cPent  0.22 (D)      CVL                     171                                                                                ##STR325##       p      rac cPent  0.37 (C)      CVLI                    172                                                                                ##STR326##       p      rac cPent                CVLII                   173                                                                                ##STR327##       p      rac cPent  0.19 (C)                                                                             FAB: 532                                                                             CVLIII                  174                                                                                ##STR328##       p      rac cPent                CIL                     175                                                                                ##STR329##       p          cPent                CIL                     176                                                                                ##STR330##       p          cPent                CIL                     177                                                                                ##STR331##       p      rac Et                   CI                      178                                                                                ##STR332##       p      rac Me                   CLI                     179                                                                                ##STR333##       p      rac nPent                CLII                    180                                                                                ##STR334##       p      diaA                                                                              nPent                CLII                    181                                                                                ##STR335##       p      diaB                                                                              nPent                CLII                    182                                                                                ##STR336##       p      rac                                                                                ##STR337##          CLIII                   183                                                                                ##STR338##       p      diA                                                                                ##STR339##          CLIII                   184                                                                                ##STR340##       p      diaB                                                                               ##STR341##          CLIII                   __________________________________________________________________________

EXAMPLE NO. 1852-(R,S)-2,4-(2,4-Dimethyl-α-carbolin-9yl)-methylphenyl!-2-cyclopentyl-aceticacid N-benzyl, N-benzoyl!-amide ##STR342##

2.0 g (4.8 mmol) of the compound from Example No. LXI are reacted with0.74 ml (5.3 mmol) of triethylamine and 0.41 ml (5.3 mmol) of mesylchloride at -30° C. in anhydrous DMF for 1 h. A solution of 1.07 g (5.1mmol) of N-benzyl-benzamide and 1.42 ml (10.2 mmol) of triethylamine in10 ml of anhydrous DMF is then added dropwise at -30° C. and stirred for16 h while gradually warming to 20° C. The reaction mixture is stirredwith ether and water, the phases are separated and the aqueous phase iswashed after setting a pH of 4 and 7 in each case. The combined organicsolutiom are evaporated and purified by chromatography on silica gel 60(Merck/first dichloromethane:ethanol=60:1; then petroleum ether:ethylacetate-4:1).

R_(f) =0.58 (Petroleum ether:ethyl acetate=2:1)

EXAMPLE NO. 186 2-(R, S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticN-benzoyl!-amide ##STR343##

2.0 g (3.3 mmol) of the compound from Example No. 185 are reacted at 20°C. under a hydrogen pressure of about 1 bar on 2 g of palladium onanimal carbon (5%) in dioxane for about 40 h. The mixture is thenfiltered off with suction through a Seitz filter and washed withdioxane, and the flitrate is evaporated. The crude product isprecipitated by stirring with methanol at 60° C. and is filtered offwith suction at 20° C., washed with cold methanol and dried overphosphorus pentoxide in vacuo.

R_(f) =0.49 (Petroleum ether:ethyl acetate=2:1)

EXAMPLE NO. 187 (R,S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methylphenyl!-2-cyclopentyl-acetic acidN-(1-(R,S)-1-phenyl-1-ethoxycarbonyl-methyl!-amide ##STR344##

The compound from Example No. LXI is reacted to give the title compoundanalogously to the procedure of Example Nos. 1, 2 and 3.

EXAMPLE NO. 188 2-(R,S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-aceticacid N-(1-(R,S)-1-phenyl-1-carboxy-methyl!-amide ##STR345##

The compound from Example No. 187 is reacted to give the title compoundanalogously to the procedure of Example No. 73.

EXAMPLE NO. 189 1-1-(R,S)-2-hydroxy-phenyl-ethyl2-(R,S)-2-4-(2,4-Dimethyl-α-carbolin-9-yl)-methyl-phenyl!-2-cyclopentyl-acetate##STR346##

1 g (2.42 mmol) of the compound from Example No. LXI is reacted with 1ml (7.27 mmol) of triethylamine and 206 μl (2.67 mmol) of mesyl chloridefor 1 h in 30 ml of DMF at -30° C. A solution of1-(R,S)-1-phenyl-2-hydroxy-thioethanol in 10 ml of DMF is then addeddropwise at the temperature mentioned and the mixture is stirred for afurther hour. For working up, the reaction mixture is stirred into etherand aqueous sodium hydrogen carbonate solution. The organic phase iswashed with buffer pH=2 and then pH=7, dried with magnesium sulphate andevaporated. The crude product is purified on silica gel 60(Merck/petroleum ether:ethyl acetate=5:1); yield: 660 mg

R_(f) =0.58 (Petroleum ether:ethyl acetate=2:1)

We claim:
 1. A cycloalkyl-indole or -azaindole derivative of the formula##STR347## in which R¹ and R² form a pyridyl ring which is optionallysubstituted 1 to 3 times by identical or different substituents;R³ andR⁴, including the double bond connecting them, form a phenyl ring or a6-membered cycloalkene ring each of which are optionally substituted 1to 3 times by identical or different substituents,wherein saidsubstituents on the pyridyl, phenyl or cycloalkene ring are selectedfrom the group consisting of halogen, trifluoromethyl, carboxylhydroxyl, straight-chain or branched C₁ -C₆ alkoxy, straight-chain orbranched C₁ -C₆ alkoxycarbonyl, or an optionally substitutedstraight-chain or branched C₁ -C₆ alkyl wherein the substituents on thealkyl group are hydroxyl or straight-chain or branched alkoxy having upto 4 carbon atoms, D represents hydrogen, cycloalkyl having 4 to 12carbon atoms or straight-chain or branched alkyl having up to 12 carbonatoms, E represents the --CO-- or --CS group, L represents a group ofthe formula --NR⁹ whereinR⁹ denotes hydrogen or straight-chain orbranched alkyl having up to 6 carbon atoms, which is optionallysubstituted by hydroxyl or phenyl, R⁵ represents phenyl which isoptionally substituted 1 to 3 times by identical or differentsubstituents selected from the group consisting of nitro, carboxyl,halogen, cyano, straight-chain or branched C₂ -C₆ alkenyl,straight-chain or branched C₁ -C₆ alkoxycarbonyl or optionallysubstituted C₁ -C₆ straight-chain or branched alkyl wherein thesubstituents on the alkyl are hydroxyl, carboxyl, straight-chain orbranched C₁ -C₆ alkoxy, straight-chain or branched C₁ -C₆ alkoxycarbonylor said phenyl ring is further optionally substituted by a group of theformula --OR.sup. or --NR¹¹ R¹², whereinR¹⁰ denotes hydrogen orstraight-chain or branched alkyl or alkenyl each having up to 6 carbonatoms, R¹¹ and R¹⁴ are identical or different and denote phenyl,hydrogen or straight-chain or branched alkyl having up to 6 carbon atomsor straight-chain or branched acyl having up to 8 carbon atoms, which isoptionally substituted by a group of the formula --NR⁻⁻ R¹⁴, whereinR¹³and R¹⁴ are identical or different and denote hydrogen or straight-chainor branched acyl having up to 8 carbon atoms, R⁶ represents hydrogen,carboxyl or straight-chain or branched alkoxycarbonyl having up to 5carbon atoms, or represents straight-chain or branched alkyl having upto 6 carbon atoms, which is optionally substituted by hydroxyl or by agroup of the formula --O--CO--R¹⁵, whereinR¹⁵ denotes phenyl which isoptionally substituted up to 3 times by identical or different halogenor hydroxyl substituents or by straight-chain or branched alkyl havingup to 5 carbon atoms, or straight-chain or branched alkyl or alkenyleach having up to 22 carbon atoms, each of which is optionallysubstituted by a group of the formula --OR¹⁶, whereinR¹⁶ is hydrogen,benzyl, triphenylmethyl or straight-chain or branched acyl having up to6 carbon atoms, R⁷ represents hydrogen or R⁶ and R⁷ together representthe group of the formula ═O, or its isomeric form or a salt thereof. 2.A cycloalkylano-indole or azaindole derivative according to claim 1,whereinR¹ and R² form a pyridyl ring which is optionally substituted 1to 2 times by identical or different substituents; R³ and R⁴, includingthe double bond connecting them, form a phenyl ring or a 6-memberedcycloalkene ring each of which are optionally substituted 1 to 2 timesby identical or different substituents,wherein said substituents on thepyridyl, phenyl or cycloalkene ring are selected from the groupconsisting of fluorine, chlorine, bromine, trifluoromethyl,carboxyl,hydroxyl, straight-chain or branched C₁ -C₄ alkoxy,straight-chain or branched C₁ -C₄ alkoxycarbonyl or optionallysubstituted straight-chain or branched C₁ -C₄ alkyl wherein thesubstituents on the alkyl group are hydroxyl or straight-chain orbranched alkoxy having up to 3 carbon atoms, D represents hydrogen,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl orstraight-chain or branched alkyl having up to 10 carbon atoms, Erepresents the --CO-- or --CS-- group, L represents a group of theformula --NR⁹, whereinR⁹ denotes hydrogen or straight-chain or branchedalkyl having up to 5 carbon atoms, which is optionally substituted byhydroxyl or phenyl, R⁵ represents phenyl, which is optionallysubstituted up to 2 times by identical or different substituentsselected from the group consisting of nitro, carboxyl, fluorine,chlorine, bromine, cyano, straight-chain or branched C₁ -C₄ alkenyl,straight-chain or branched C₁ -C₄ alkoxycarbonyl or optionallysubstituted straight-chain or branched C₁ -C₄ alkyl wherein thesubstituents on alkyl group are hydroxyl, carboxyl or by straight-chainor branched alkoxy or alkoxycarbonyl each having up to 5 carbon atoms,or said phenyl ring is optionally further substituted by a group of theformula --OR¹⁰ or --NR¹¹ R¹², whereinR¹⁰ denotes hydrogen orstraight-chain or branched alkyl or alkenyl each having up to 4 carbonatoms, R¹¹ and R¹² are identical or different and denote phenyl,hydrogen or straight-chain or branched alkyl having up to 5 carbon atomsor denote straight-chain or branched acyl having up to 6 carbon atoms,which is optionally substituted by a group of the formula --NR¹³ R¹⁴,whereinR¹³ and R¹⁴ are identical or different and denote hydrogen orstraight-chain or branched acyl having up to 6 carbon atoms, R⁶represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 4 carbon atoms, or represents straight-chainor branched alkyl having up to 5 carbon atoms, which is optionallysubstituted by hydroxyl or by a group of the formula --O--CO--R¹⁵,whereinR¹⁵ denotes phenyl which is optionally substituted up to 3 timesby identical or different fluorine, chlorine, bromine or hydroxylsubstituents or by straight-chain or branched alkyl having up to 4carbon atoms, or straight-chain or branched alkyl or alkenyl each havingup to 20 carbon atoms, each of which is optionally substituted by agroup of the formula --OR¹⁶, whereinR¹⁶ is hydrogen, benzyl,triphenylmethyl or straight-chain or branched acyl having up to 5 carbonatoms, R⁷ represents hydrogen or R⁶ and R⁷ together represent the groupof the formula ═O, or its isomeric form or a salt thereof.
 3. Acycloalkano-indole or -azaindole derivative according to claim 1,whereinR¹ and R² form a pyridyl ring which is optionally substituted 1to 2 times by identical or different substituents; R³ and R⁴, includingthe double bond connecting them, form a phenyl ring or a 6-memberedcycloalkene ring each of which are optionally substituted 1 to 2 timesby identical or different substituents,wherein said substituents on thepyridyl, phenyl or cycloalkene ring are selected from the groupconsisting of fluorine, chlorine, bromine, trifluoromethyl, carboxyl,hydroxyl, straight-chain or branched C₁ -C₃ alkoxy, straight-chain orbranched C₁ -C₃ alkoxycarbonyl or optionally substituted straight-chainor branched C₁ -C₃ alkyl, wherein the substituents or the alkyl groupsare hydroxyl, methoxy or ethoxy, D represents hydrogen, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl or straight-chain or branched alkylhaving up to 6 carbon atoms, E represents the --CO-- or --CS-- group, Lrepresents a group of the formula --NR⁹, whereinR⁹ denotes hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms, which isoptionally substituted by hydroxyl or phenyl, R⁵ represents phenyl,which is optionally substituted up to 2 times by identical or differentsubstituents selected from the group consisting of nitro, carboxyl,fluorine, chlorine, bromine, cyano, C₁ -C₃ alkenyl, straight-chain orbranched C₁ -C₃ alkoxycarbonyl or optionally substituted straight-chainor branched C₁ -C₄ alkyl wherein the substituents are hydroxyl,carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl eachhaving up to 4 carbon atoms, or said phenyl ring is optionally furthersubstituted by a group of the formula --OR¹⁰ or --NR¹¹ R¹², whereinR¹⁰denotes hydrogen or straight-chain or branched alkyl or alkenyl eachhaving up to 3 carbon atoms, R¹¹ and R¹² are identical or different anddenote phenyl, hydrogen or straight-chain or branched alkyl having up to4 carbon atoms or denote straight-chain or branched acyl having up to 5carbon atoms, which is optionally substituted by a group of the formula--NR¹³ R¹⁴, whereinR¹³ and R¹⁴ are identical or different and denotehydrogen or straight-chain or branched acyl having up to 5 carbon atoms,R⁶ represents hydrogen, carboxyl or straight-chain or branchedalkoxycarbonyl having up to 3 carbon atoms, or represents straight-chainor branched alkyl having up to 4 carbon atoms, which is optionallysubstituted by hydroxyl or by a group of the formula --O--CO--R¹⁵,whereinR¹⁵ denotes phenyl which is optionally substituted up to 3 timesby identical identical or different straight-chain or branched alkylhaving up to 3 carbon atoms, or denotes straight-chain or branched alkylor alkenyl each having up to 19 carbon atoms, each of which isoptionally substituted by a group of the formula --OR¹⁶, whereinR¹⁶denotes hydrogen, benzyl, triphenylmethyl or straight-chain or branchedacyl having up to 4 carbon atoms, R⁷ represents hydrogen or R⁶ and R⁷together represent the group of the formula ═O,or its isomeric form or asalt thereof.
 4. A cycloalkane-indole or -azaindole derivative accordingto claim 1, whereinR¹ and R² form a pyridyl ring which is optionallysubstituted 1 to 3 times by identical or different substituents; R³ andR⁴, including the double bond connecting them, form a phenyl ring or a6-membered cycloalkene ring each of which are optionally substituted 1to 3 times by identical or different substituents,wherein saidsubstituents on the pyridyl, phenyl or cycloalkene ring are selectedfrom the group consisting of fluorine, chlorine, bromine,trifiuoromethyl, carboxyl, hydroxyl, straight-chain or branched C₁ -C₄alkoxy, straight-chain or C₁ -C₄ alkoxycarbonyl optionally substitutedstraight-chain or branched C₁ -C₄ alkyl wherein the substituents on thealkyl group are hydroxyl or straight-chain or branched alkoxy having upto 3 carbon atoms, D represents hydrogen, cycloalkyl having 4 to 12carbon atoms or straight-chain or branched alkyl having up to 12 carbonatoms, E represents the --CO-- or --CS group, L represents a group ofthe formula --NR⁹ whereinR₉ denotes hydrogen or straight-chain orbranched alkyl having up to 6 carbon atoms, which is optionallysubstituted by hydroxyl or phenyl, R⁵ represents phenyl which isoptionally substituted 1 to 3 times by identical or differentsubstituents selected from the group consisting of nitro, carboxyl,halogen, cyano straight-chain or branched C₂ -C₆ alkenyl, straight-chainor branched C₁ -C₆ alkoxycarbonyl or optionally substituted C₁ -C₆straight-chain or branched alkyl wherein the substituents on the alkylare hydroxyl, carboxyl, straight-chain or branched C₁ -C₆ alkoxy,straight-chain or branched C₁ -C₆ alkoxycarbonyl or said phenyl ring isfurther optionally substituted by a group of the formula --OR¹⁰ or--NR¹¹ R¹¹, whereinR¹⁰ denotes hydrogen or straight-chain or branchedalkyl or alkenyl each having up to 6 carbon atoms, R¹¹ and R¹² areidentical or different and denote phenyl, hydrogen or straight-chain orbranched alkyl having up to 6 carbon atoms or straight-chain or branchedacyl having up to 8 carbon atoms, which is optionally substituted by agroup of the formula --NR¹³ R¹⁴, whereinR¹³ and R¹⁴ are identical ordifferent and denote hydrogen or straight-chain or branched acyl havingup to 8 carbon atoms, R⁶ represents hydrogen or a straight-chain orbranched alkyl having up to 6 carbon atoms which is optionallysubstituted by hydroxyl, R⁷ represents hydrogenor its isomeric or a saltthereof.
 5. A cycloalkane-indole or -azaindole derivative according toclaim 1, whereinR¹ and R² form a pyridyl ring which is optionallysubstituted 1 to 3 times by identical or different substituents; R³ andR⁴, including the double bond connecting them, form a phenyl ring or a6-membered cycloalkene ring each of which are optionally substituted 1to 3 times by identical or different substituents,wherein saidsubstituents on the pyridyl, phenyl or cycloalkene ring are selectedfrom the group consisting of fluorine, chlorine, bromine,trifiuoromethyl, carboxyl,hydroxyl, straight-chain or branched C₁ -C₄alkoxy, straight-chain or C₁ -C₄ alkoxycarbonyl optionally substitutedstraight-chain or branched C₁ -C₄ alkyl wherein the substituents on thealkyl group are hydroxyl or straight-chain or branched alkoxy having upto 3 carbon atoms, D represents hydrogen, cycloalkyl having 4 to 12carbon atoms or straight-chain or branched alkyl having up to 12 carbonatoms, E represents the --CO-- or --CS group, L represents a group ofthe formula --NR⁹ whereinR⁹ denotes hydrogen or straight-chain orbranched alkyl having up to 6 carbon atoms, which is optionallysubstituted by hydroxyl or phenyl, R⁵ represents phenyl which isoptionally substituted 1 to 3 times by identical or differentsubstituents selected from the group consisting of nitro, carboxyl,halogen, cyano or straight-chain or branched C₂ -C₆ alkenyl,straight-chain or branched C_(1-C) ₆ alkoxycarbonyl or optionallysubstituted C₁ -C₆ straight-chain or branched alkyl wherein thesubstituents on the alkyl are hydroxyl, carboxyl, straight-chain orbranched C₁ -C₆ alkoxy, straight-chain or branched C₁ -C₆ alkoxycarbonylor said phenyl ring is further optionally substituted by a group of theformula --OR¹⁰ or --NR¹¹ R¹², wherein represents straight-chain orbranched alkyl having up to 6 carbon atoms which is substituted byhydroxyl, or its isomeric or salt thereof.
 6. The compound according toclaim 1, where such compound is ##STR348## or its isomer, racemicmixture, or salt thereof.
 7. The compound according to claim 1, whereinsuch compound is ##STR349## or an isomer, racemic mixture or saltthereof.
 8. The compound according to claim 1, wherein such compound is##STR350## or an isomer, racemic mixture or salt thereof.
 9. Thecompound according to claim 1, wherein such compound is ##STR351## or anisomer, racemic mixture or salt thereof.
 10. A composition for thetreatment of atherosclerosis comprising an amount effective therefor ofa compound or salt thereof according to claim 1 and a pharmacologicallyacceptable diluent.
 11. The method of treating atherosclerosis in apatient in need thereof which comprises administering to such patient anamount effective therefor of a compound or salt thereof according toclaim 1.